Hydroxamic acid derivatives, process for the production thereof and drug containing the same as the active ingredient

ABSTRACT

Hydroxamic acid derivatives of the formula (I)                    
     (wherein all the symbols have the same meaning as defined in the specification.), 
     non-toxic salt thereof or prodrugs thereof. 
     The compounds of the formula (I) inhibit producing IL-6, so it may be used for the prevention and/or treatment of various inflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi&#39;s sarcoma, rheumatoid arthritis, hypergammaglobulinemia, Castleman&#39;s disease, atrial myxoma, diabetes mellitus, autoimmune diseases, hepatitis, colitis, graft versus host disease, infectious diseases and endometriosis.

TECHNICAL FIELD

The present invention relates to hydroxamic acid derivatives, themethods for preparation thereof and inhibitors of interleukin-6production comprising thereof, as an active ingredient.

More particularly, it relates to (1) inhibitors of IL-6 productioncomprising hydroxamic acid derivatives of the formula (I)

(wherein all the symbols have the same meaning as defined hereinafter),non-toxic salts thereof and prodrugs thereof, as an active ingredient,

(2) novel hydroxamic acid derivatives of the above formula (I),non-toxic salts thereof and prodrugs thereof and

(3) the methods for preparation of hydroxamic acid derivatives of theabove formula (I), non-toxic salts thereof and prodrugs thereof.

BACKGROUND

Cytokine is a multifunctional factor which plays an important role inthe host defense system of living body and it relates to various lifephenomena. However, there are many diseases which may be caused byoverproduction thereof or overresponse thereto.

IL-6 is a cytokine produced from various cells, e.g. T cells, B cells,macrophages, kidney mesangial cells, fibroblasts, and its variousphysiological effects are known e.g. induction of B cellsdifferentiation to antibody-producing cells, activation of T cells,increase of platelets, and production of acute phase protein from livercells. But an abnormal production of IL-6 has been observed in variousinflammations, autoimmune diseases and neoplastic diseases and it issuggested that IL-6 plays a certain role in the causes of suchpathophysiological situations. In the experiment using an animal modelin which IL-6 was forcibly expressed, various types of diseases could beobserved and such results strongly suggest the existence of relationshipbetween the abnormal production of IL-6 and the cause of certaindiseases (Biochem. J., 265, 621 (1990), Immunol. Today, 11, 443 (1990),J. Autoimmun., 5 Suppl A, 123 (1992), Clin. Immunol. Immunopathol., 62,S60 (1992)).

Therefore inhibition of IL-6 production is expected to improve variouskinds of diseases such as inflammatory diseases as a representative. Thepresent invention is targeted for the cytokine and provides novelmedicines through inhibiting the production thereof.

Clinical application of the compounds of the present invention involvesthose diseases which may be caused and be changed to worse by abnormalproduction of IL-6 or by overresponse to them. Inhibitors of IL-6production may be used for the prevention and/or treatment of variousinflammatory diseases, sepsis, multiple myeloma, plasma cell leukemia,osteoporosis, cachexia, psoriasis, nephritis, renal cell carcinoma,Kaposi's sarcoma, rheumatoid arthritis, hypergammaglobulinemia,Castleman's disease, atrial myxoma, diabetes mellitus, autoimmnediseases, hepatitis, colitis, graft versus host disease, infectiousdiseases and endometriosis (J. Immunol., 145, 4185 (1990), J. Exp. Med.,172, 1505 (1990), J. Clin. Invest., 87, 739 (1991), J. Clin. Invest.,89, 1681 (1992), EMBO J., 13, 1189 (1994), Hematol. Oncol. Clin. NorthAm., 11, 159 (1997), Cytokines Cell Mol. Ther., 4(3), 161 (1998), FoliaMed. (Plovdiv), 41(1), 78 (1999), JPEN J. Parenter Enteral Nutr., 23(5),S20 (1999), J. Infect. Dis., 180(1), 10 (1999), Am. J. Obstet. Gynecol.,176(3), 593 (1997)).

For example, in the specification of Japanese Patent Application KokaiS59-46244, it is described that hydroxamic acid derivatives of theformula (X)

A^(X)—B^(X)—(CH₂)_(nX)—CONHOH  (X)

[wherein A^(X) is R^(X)X^(X)m^(X) (R^(X) is phenyl, pyrrolyl, thienyl,imidazolyl or thiazolyl, X^(X) is halogen, lower alkyl, lower alkoxy ornitro, m^(X) is 0 or an integer of 1-2 and each X^(X) is the same ordifferent optionally.), B^(X) is —CHOH—, —CH—, —O— or —CO, nX is aninteger of 2-10.]

is useful as anti-parasite agent.

And in the U.S. Pat. No. 4,769,461, it is described that hydroxamic acidderivatives of the formula (Y)

[wherein W^(Y) is a bond, —O—, —S—, —NR^(2Y)—, —CH(OH)—or —NR^(2Y) —CO—,X^(Y) is N or CR^(2Y),

when nY=0, Y^(Y) is O, S, NR^(2Y) or C(R^(2Y))₂

when nY=1, Y^(Y) is N or CR^(2Y),

Z^(Y) is —CH₂O—, —CH₂S—, —CH₂NR^(2y)—, —O—, —S—, —NR²—, —CO—,—CONR^(2Y—, —CHR) ^(2Y)CHR^(2Y)—, —C(R^(2Y))═C(R^(2Y))— or —C≡C—,

R^(1Y) is hydrogen, lower alkyl, trifluoromethyl, nitro, hydroxy, loweralkoxy, mercapto, lower alkylthio or halogen,

R^(2Y) is hydrogen or lower alkyl,

nY is 0 or 1,

mY is 1-6.

With the proviso that when W^(Y) is a bond, then mY is 0-5.]

is useful as antiinflammatory or anti-allergy agent by inhibition ofcyclooxygenase and lipoxygenase.

DISCLOSURE OF THE INVENTION

Energetic investigations have been carried out to discover a compoundpossessing an inhibitory activity of IL-6 production. As a results, thepresent inventors have found that the purpose has been achieved byhydroxamic acid derivatives of the formula (I) or non-toxic saltsthereof.

Hydroxamic acid derivatives of the formula (I) of the present inventionhave not been known as inhibitors of IL-6 production at all. Further,almost hydroxamic acid derivatives of the formula (I), non-toxic saltsthereof and prodrugs thereof are novel compounds which are not known atall.

The present invention relates to

1) an inhibitor of IL-6 production comprising hydroxamic acidderivatives of the formula (I),

[wherein, R¹ is

(a) C1-8 alkyl,

(b) C2-8 alkenyl,

(c) C2-8 alkynyl,

(d) halogen,

(e) nitro,

(f) nitrile,

(g) trifluoromethyl,

(h) trifluoromethoxy,

(i) —OR²,

(j) —SR²,

(k) —NR³R⁴,

(l) —COR⁵,

(m) keto,

(n) Cyc1,

(o) C1-8 alkyl substituted by —OR², —SR², —NR³R⁴, —COR⁵ or Cyc1,

(p) —SO₂R¹⁰,

(q) (C1-8 alkylene)—OR¹¹,

(r) C1-8 alkyl substituted by nitrile, —SO₂R¹⁰ or —O—(C1-8alkylene)—OR¹¹,

(s) —O—(C1-8 alkylene)—NR¹²R¹³,

(t) —S—(C1-8 alkylene)—NR¹²R¹³,

(u) C1-8 alkyl substituted by —O—(C1-8 alkylene)—NR¹²R¹³— or —S—(C1-8alkylene)—NR¹²R¹³,

(v) C2-8 alkenyl substituted by —OR², —SR², —NR³R⁴, —COR⁵, Cyc1,nitrile, —SO₂R¹⁰, —O—(C1-8 alkylene)—OR¹¹, —O—(C1-8 alkylene)—NR¹²R¹³ or—S—(C1-8 alkylene)—NR¹²R¹³ or

(w) C2-8 alkynyl substituted by —OR², —SR², —NR³R⁴, —COR⁵, Cyc1,nitrile, —SO₂R¹⁰, —O—(C1-8 alkylene)—OR¹¹, —O—(C1-8 alkylene)—NR¹²R¹³ or—S—(C1-8 alkylene)—NR¹²R¹³,

R² is hydrogen, C1-8alkyl, C2-9 acyl or Cyc1,

R³ and R⁴ are each independently hydrogen, C1-8 alkyl, C2-9 acyl orCyc1,

R⁵ is hydroxy, C1-8 alkyl, C1-8 alkoxy, —NR⁶R⁷ or Cyc1,

R⁶ and R⁷ are each independently hydrogen, C1-8 alkyl or Cyc1,

R¹⁰ is C1-8 alkyl or Cyc1,

Cyc1 is C3-7 monocarbocyclic ring or 5-7 membered mono-cyclic heteroring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfuratom,

R¹¹ is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,

R¹² and R¹³ are each independently hydrogen, C1-8 alkyl, C2-9 acyl orCyc1,

m is 0 or an integer of 1-5,

ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 memberedmono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s),1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),

ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 memberedmono-, bi- or tricyclic hetero aryl containing 1-4 nitrogen atom(s), 1-2oxygen atom(s) and/or 1-2 sulfur atom(s),

E is a bond, —CH═CH— or —C≡C—,

R⁸ is

(a) C1-8 alkyl,

(b) C1-8 alkoxy,

(c) halogen,

(d) nitro,

(e) nitrile,

(f) trifluoromethyl or

(g) trifluoromethoxy.

With the proviso that when E is a bond, then R¹ and R⁸, taken together,may be optionally C1-4 alkylene.

n is 0 or an integer of 1-5,

R⁹ is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl.],

nontoxic salts thereof or prodrugs thereof, as an active ingredient,

2) Hydroxamic acid derivatives of the formula (I)

[wherein, R¹ is

(a) C1-8 alkyl,

(b) C2-8 alkenyl,

(c) C2-8 alkynyl,

(d) halogen,

(e) nitro,

(f) nitrile,

(g) trifluoromethyl,

(h) trifluoromethoxy,

(i) —OR²,

(j) —SR²,

(k) —NR³R⁴,

(l) —COR⁵,

(m) keto,

(n) Cyc1,

(o) C1-8 alkyl substituted by —OR², —SR², —NR³R⁴, —COR⁵ or Cyc1,

(p) —SO₂R¹⁰,

(q) —O—(C1-8 alkylene)—OR¹¹,

(r) C1-8 alkyl substituted by nitrile, —SO₂R¹⁰ or —O—(C1-8alkylene)—OR¹¹,

(s) —O—(C1-8 alkylene)—NR¹²R¹³,

(t) —S—(C1-8 alkylene)—NR¹²R¹³,

(u) C1-8 alkyl substituted by —O—(C1-8 alkylene)—NR¹²R¹³— or —S—(C1-8alkylene)—NR¹²R¹³,

(v) C2-8 alkenyl substituted by —OR², —SR², —NR³R⁴, —COR⁵, Cyc1,nitrile, —SO₂R¹⁰, —O—(C1-8 alkylene)—OR¹¹, —O—(C1-8 alkylene)—NR¹²R¹³ or—S—(C1-8 alkylene)—NR¹²R¹³ or

(w) C2-8 alkynyl substituted by —OR², —SR², —NR³R⁴, —COR⁵, Cyc1,nitrile, —SO₂R¹⁰, —O—(C1-8 alkylene)—OR¹¹, —O—(C1-8 alkylene)—NR¹²R¹³ or—S—(C1-8 alkylene)—NR¹²R¹³ or

R² is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,

R³ and R⁴ are each independently hydrogen, C1-8 alkyl, C2-9 acyl orCyc1,

R⁵ is hydroxyl, C1-8 alkyl, C1-8 alkoxy, —NR⁶R⁷ or Cyc1,

R⁶ and R⁷ are each independently hydrogen, C1-8 alkyl or Cyc1,

R¹⁰ is C1-8 alkyl or Cyc1,

Cyc1 is C3-7 mono-carbocyclic ring or 5-7 membered mono-cyclic heteroring containing 1-4 nitrogen atom(s), one oxygen atom and/or one sulfuratom,

R¹¹ is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1,

R¹² and R¹³ are each independently hydrogen, C1-8 alkyl, C2-9 acyl orCyc1,

m is 0 or an integer of 1-5,

ring A is C3-15 mono-, bi- or tri-carbocyclic ring or 5-18 memberedmono-, bi- or tri-cyclic hetero ring containing 1-4 nitrogen atom(s),1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),

ring B is C5-15 mono-, bi- or tri-carbocyclic aryl or 5-18 memberedmono-, bi- or tri-cyclic hetero aryl containing 1-4 nitrogen atom(s),1-2 oxygen atom(s) and/or 1-2 sulfur atom(s),

E is a bond, —CH═CH— or —C≡C—,

R⁸ is

(a) C1-8 alkyl,

(b) C1-8 alkoxy,

(c) halogen,

(d) nitro,

(e) nitrile,

(f) trifluoromethyl or

(g) trifluoromethoxy.

With the proviso that when E is a bond then R¹ and R⁸, taken together,is C1-4 alkylene optionally.

n is 0 or an integer of 1-5,

R⁹ is hydrogen, C1-8 alkyl, C2-8 alkenyl or C2-8 alkynyl.

With the proviso that when E is —CH═CH— or —C≡C—, ring A is C3-7mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom.],

nontoxic salts thereof or prodrugs thereof,

3) the methods for preparation of hydroxamic acid derivatives of theabove formula (I), non-toxic salts thereof and prodrugs thereof.

DETAILED EXPLANATION OF THE INVENTION

Unless otherwise specified, all isomers are included in the presentinvention. For example, alkyl, alkoxy and alkylene groups includestraight or branched ones. In addition, isomers on double bond, ring,fused ring (E-, Z-, cis-, trans-isomer), isomers generated fromasymmetric carbon atom(s) (R-, S-, α-, β-isomer, enantiomer,diastereomer), optically active isomer (D-, L-, d-, l-, (+)-,(−)-isomer), polar compounds generated by chromatographic separation(more polar compound, less polar compound), equilibrium compounds,mixtures thereof at voluntary ratios and racemic mixtures are alsoincluded in the present invention.

In the present invention, C1-8 alkyl means methyl, ethyl, propyl, butyl,pentyl, hexyl, heptyl, octyl and the isomers thereof.

C2-8 alkenyl means vinyl, propenyl, butenyl, pentenyl, hexenyl,heptenyl, octenyl, butadienyl, pentadienyl, hexadienyl, heptadienyl,octadienyl, hexatrienyl, heptatrienyl, octatrienyl and the isomerthereof.

C2-8 alkynyl means ethynyl, propynyl, butynyl, pentynyl, hexynyl,heptynyl, octynyl, butadiynyl, pentadiynyl, hexadiynyl, heptadiynyl,octadiynyl, hexatriynyl, heptatriynyl, octatriynyl and the isomerthereof.

Halogen means fluoride, chloride, bromide and iodide.

C1-4 alkylene means methylene, ethylene, trimethylene, tetramethyleneand the isomers thereof.

C1-8 alkylene means methylene, ethylene, trimethylene, tetramethylene,pentamethylene, hexamethylene, heptamethylene, octamethylene and isomersthereof.

C2-9 acyl means acetyl, propionyl, butyryl, valeryl, hexanoyl,heptanoyl, octanoyl, nonanoyl and the isomers thereof.

C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy,heptyloxy, octyloxy and the isomers thereof.

C3-7 mono-carbocyclic ring means C3-7 mono-aromatic carbocyclic ring,partially saturated carbocyclic ring thereof and fully saturatedcarbocyclic ring thereof. It includes, for example, cyclopropane,cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclopentene,cyclohexene, cycloheptene, cyclopentadiene, cyclohexadiene,cycloheptadiene and benzene etc.

5-7 membered mono-cyclic hetero ring containing 1-4 nitrogen atom(s),one oxygen atom and/or one sulfur atom means 5-7 membered mono-cyclichetero aryl containing 1-4 nitrogen atom(s), one oxygen atom and/or onesulfur atom and partially or fully saturated one. It includes, forexample, pyrrole, imidazole, pyrazole, triazole, tetrazole, pyridine,pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran,oxepine, oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole,isoxazole, thiazole, isothiazole, oxadiazole, oxazine, oxadiazine,oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, pyrroline, pyrrolidine, imidazoline, imidazolidine,pyrazoline, pyrazolidine, triazoline, triazolidine, tetrazoline,tetrazolidine, dihydropyridine, dihydropyrimidine, dihydropyridazine,piperidine, piperazine, tetrahydropyrimidine, tetrahydropyridazine,dihydroazepine, dihydrodiazepine, tetrahydroazepine,tetrahydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran,tetrahydropyran, dihydrothiophene, tetrahydrothiophene, dihydrothiain(dihydrothiopyran), tetrahydrothiain (tetrahydrothiopyran),dihydrooxazole, tetrahydrooxazole, dihydroisoxazole,tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole,dihydroisothiazole, tetrahydroisothiazole, tetrahydroxadiazole,tetrahydroxazine, tetrahydroxadiazine, tetrahydroxazepine,tetrahydroxadiazepine, tetrahydrothiadiazole, tetrahydrothiazine,tetrahydrothiadiazine, tetrahydrothiazepine, tetrahydrothiadiazepine,morpholine and thiomorpholine etc.

C3-15 mono-, bi- or tri-carbocyclic ring means C3-15 mono-, bi- andtri-aromatic carbocyclic ring, partially saturated carbocyclic ringthereof and fully saturated carbocyclic ring thereof. It includes, forexample, cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene,cyclohexadiene, cycloheptadiene, benzene, pentalene, indene,naphthalene, azulene, fluorene, phenanthrene, anthracene,acenaphthylene, biphenylene, perhydropentalene, perhydroindene,dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene,perhydroazulene, perhydrofluorene, perhydrophenanthrene,perhydroanthracene, perhydroacenaphthylene and perhydrobiphenylene, etc.

5-18 membered mono-, bi- or tri-cyclic hetero ring containing 1-4nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) means5-18 membered mono-, bi- or tri-cyclic hetero aryl containing 1-4nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) andpartially or fully saturated one. It includes, for example, pyrrole,imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,oxazepine, thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole,thiazole, isothiazole, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzimidazole, carbazole, acridine,dibenzofuran, dibenzothiophene, pyrroline, pyrrolidine, imidazoline,imidazolidine, pyrazoline, pyrazolidine, triazoline, triazolidine,tetrazoline, tetrazolidine, dihydropyridine, dihydropyrimidine,dihydropyridazine, piperidine, piperazine, tetrahydropyrimidine,tetrahydropyridazine, dihydroazepine, dihydrodiazepine,tetrahydroazepine, tetrahydrodiazepine, dihydrofuran, tetrahydrofuran,dihydropyran, tetrahydropyran, dihydrothiophene, tetrahydrothiophene,dihydrothiain (dihydrothiopyran), tetrahydrothiain(tetrahydrothiopyran), dihydrooxazole, tetrahydrooxazole,dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole,tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole,tetrahydrooxadiazole, tetrahydrooxazine, tetrahydrooxadiazine,tetrahydrooxazepine, tetrahydrooxadiazepine, tetrahydrothiadiazole,tetrahydrothiazine, tetrahydrothiadiazine, tetrahydrothiazepine,tetrahydrothiadiazepine, morpholine, thiomorpholine, indoline,isoindoline, dihydrobenzofuran, perhydrobenzofuran,dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene,perhydrobenzothiophene, dihydroisobenzothiophene,perhydroisobenzothiophene, dihydroindazole, dihydroquinoline,tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline,tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine,tetrahydrophthalazine, perhydrophthalazine, dihydronaphthyridine,tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline,tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline,tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline,tetrahydrocinnoline, perhydrocinnoline, dihydrobenzoxazole,perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole,dihydrobenzimidazole, perhydrobenzimidazole, benzoxazepine,benzoxadiazepine, benzothiazepine, benzothiadiazepine, benzazepine,benzodiazepine, indroxoazepine, indrotetrahydroxazepine,indroxadiazepine, indrotetrahydroxadiazepine, indrothiazepine,indrotetrahydrothiazepine, indrothiadiazepine,indrotetrahydrothiadiazepine, indroazepine, indrotetrahydroazepine,indrodiazepine, indrotetrahydrodiazepine, benzofurazan,benzothiadiazole, benzotriazole, imidazothiazole, dihydrocarbazole,tetrahydrocarbazole, perhydrocarbazole, dihydroacridine,tetrahydroacridine, perhydroacridine, dihydrodibenzofuran,dihydrodibenzothiophene, tetrahydrodibenzofuran,tetrahydrodibenzothiophene, perhydrodibenzofuran,perhydrodibenzothiophene, 1,3-dioxaindan and1,4-dioxotetrahydronaphthalene.

C5-15 mono-, bi- or tri-carbocyclic aryl means cyclopentadiene,cyclohexadiene, cycloheptadiene, cycloheptatriene, benzene, indene,naphthalene, fluorene and anthracene etc.

5-18 membered mono-, bi- or tri-cyclic hetero aryl containing 1-4nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfur atom(s) meanspyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine,pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepine,thiophene, thiain (thiopyran), thiepine, oxazole, isoxazole, thiazole,isothiazole, furazan, oxadiazole, oxazine, oxadiazine, oxazepine,oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine,thiadiazepine, indole, isoindole, benzofuran, isobenzofuran,benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline,phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline,benzoxazole, benzothiazole, benzimidazole, benzoxepine, benzoxazepine,benzoxadiazepine, benzothiepine, benzothiazepine, benzothiadiazepine,benzazepine, benzodiazepine, benzofurazan, benzothiadiazole,benzotriazole, carbazole, acridine, dibenzofuran and dibenzothiophene.

In the present invention, unless otherwise specified, as will beapparent to those skilled in the art, a symbol represents bonding toback of the paper (that is, α-configuration), represents bonding tofront of the paper (that is, β-configuration), represents α-, β- ormixture thereof and represents mixture of α-configuration andβ-configuration.

[Salts]

Non-toxic salts of the present invention include all non-toxic salts,for example, general salts, acid addition salts, hydrate salts.

The compounds of the present invention may be converted into thecorresponding salts by conventional means. Water-soluble salts arepreferred. Suitable salts, for example, include:

salts of alkali metals (e.g. potassium, sodium), salts of alkaline earthmetals (e.g. calcium, magnesium), ammonium salts, salts ofpharmaceutically acceptable organic amines (e.g. tetramethylammonium,triethylamine, methylamine, dimethylamine, cyclopentylamine,benzylamine, phenethylamine, piperidine, monoethanolamine,diethanolamine, tris(hydroxymethyl)amine, lysine, arginine,N-methyl-D-glucamine).

The compounds of the present invention may be converted into thecorresponding acid addition salts by conventional means. Water-solublesalts are preferred. Suitable salts, for example, include:

salts of inorganic acids e.g. hydrochloride, hydrobromide, sulfate,phosphate, nitrate; salts of organic acids e.g. acetate,trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate,citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,toluenesulfonate, isethionate, glucuronate, gluconate.

The compounds of the present invention and salts thereof may beconverted into the corresponding hydrates by conventional means.

Furthermore, the prodrugs of the present invention means the compoundsthat —CONHOH group of the formula (I) is converted to

(wherein, R¹⁴ is C1-8 alkyl substituted by C1-8 alkyl or C1-8 alkoxy) or

Among the compounds of the present invention, preferred ring A is C3-10mono-, bi-carbocyclic ring or 5-10 membered mono-, bi-cyclic hetero ringcontaining 1-4 nitrogen atom(s), 1-2 oxygen atom(s) and/or 1-2 sulfuratom(s). Especially, C5-7 mono-carbocyclic ring or 5-10 membered mono-,bi-cyclic hetero ring containing 1-4 nitrogen atom(s), 1-2 oxygenatom(s) and/or 1-2 sulfur atom(s) is preferable. Benzene, cyclohexane,benzoxazole, benzothiazole, benzimidazole, benzothiophene or benzofuranis more preferable.

Preferred R¹ is (1) C1-8 alkyl, (2) —OR², (3) —SR², (4) halogen, (5)Cyc1, (6) —NR³R⁴ or (7) C1-8 alkyl substituted by —OR², —SR², halogen,Cyc1, —NR³R⁴. Especially, (1) C1-8 alkyl, (2) C1-8 alkoxy, (3) C1-8alkylthio, (4) halogen, (5) 5-7 membered mono-cyclic hetero ringcontaining 1-4 nitrogen atom(s), one oxygen atom and/or one sulfur atom,(6) di(C1-8 alkyl)amino or (7) C1-8 alkyl substituted by C1-8 alkoxy,C1-8 alkylthio, halogen, 5-7 membered mono-cyclic hetero ring, di(C1-8alkyl)amino is preferable. Methyl, methoxy, methylthio, chloride,dimethylamino, dipropylamino, morpholine, piperidine, piperazine,methoxymethyl, methylthiomethyl, dimethylaminomethyl,dipropylaminomethyl, morpholine-1-ylmethyl, piperidine-1-ylmethyl orpiperazine-1-ylmethyl is more preferable.

Preferred stereoisomer of hydroxy group is R configuration, Sconfiguration or mixture thereof. Especially, R or S configuration ispreferable. S configuration is more preferable.

Preferred E is, preferably, a bond, —CH═CH— or —C≡C— and a bond or —C≡C—is preferable.

Preferred B ring is C1-5 mono- or bi-carbocyclic aryl or 5-15 memberedmono- or bi-cyclic hetero aryl. Especially, benzene, naphthalene,pyridine, thiophene, benzofuran or benzoxazole is preferable.

Preferred R⁸ is C1-4 alkyl. Especially, methyl is preferable.

Preferred R⁹ is hydrogen, C1-4 alkyl, C2-4 alkenyl or C2-4 alkynyl.Especially, hydrogen, methyl or allyl is preferable.

Preferred m is 0 or an integer of 1-5. Especially, 0 or 1 is preferable.

Preferred n is 0 or an integer of 1-5. Especially, 0 or 1 is preferable.

In the present invention, preferred compounds are compounds prepared inexample hereinafter, shown in the following table 1 to 7 and saltsthereof etc.

TABLE 1 (I-1)

No.

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

TABLE 2 (I-1)

No.

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

13

14

15

16

17

18

19

20

TABLE 3 (I-1)

No.

 1

 2

 3

 4

 5

 6

 7

 8

 9

10

11

12

TABLE 4 (I-2)

No.

1

2

3

4

5

6

7

8

TABLE 5 (I-3)

No. R¹  1

 2

 3

 4

 5

 6

 7

 8 3-CH₂—N(CH₃)₂  9 2-CH₂—N(CH₃)₂ 10 4-(CH₂)₂—N(CH₂CH₂CH₃)₂ 113-(CH₂)₂—N(CH₂CH₂CH₃)₂ 12 2-(CH₂)₂—N(CH₂CH₂CH₃)₂ 13 3-CH₂—N(CH₂CH₂CH₃)₂14 2-CH₂—N(CH₂CH₂CH₃)₂ 15 4-O—(CH₂)₂—N(CH₂CH₂CH₃)₂ 164-S—(CH₂)₂—N(CH₂CH₂CH₃)₂ 17 4-O—(CH₂)₂—N(CH₃)₂ 18 4-S—(CH₂)₂—N(CH₃)₂

TABLE 6 (I-4)

No. R¹  1

 2

 3

 4

 5

 6

 7

 8

 9

10 4-(CH₂)₂—N(CH₃)₂ 11 3-(CH₂)₂—N(CH₃)₂ 12 2-(CH₂)₂—N(CH₃)₂ 134-(CH₂)₂—N(CH₂CH₂CH₃)₂ 14 3-(CH₂)₂—N(CH₂CH₂CH₃)₂ 152-(CH₂)₂—N(CH₂CH₂CH₃)₂ 16 4-CH₂—N(CH₂CH₂CH₃)₂ 17 3-CH₂—N(CH₂CH₂CH₃)₂ 182-CH₂—N(CH₂CH₂CH₃)₂ 19 4-O—(CH₂)₂—N(CH₂CH₂CH₃)₂ 204-S—(CH₂)₂—N(CH₂CH₂CH₃)₂ 21 4-O—(CH₂)₂—N(CH₃)₂ 22 4-S—(CH₂)₂—N(CH₃)₂

TABLE 7 (I-5)

No. R¹  1

 2

 3

 4

 5

 6

 7

 8

 9

10 4-CH₂—N(CH₃)₂ 11 3-CH₂—N(CH₃)₂ 12 2-CH₂—N(CH₃)₂ 134-(CH₂)₂—N(CH₂CH₂CH₃)₂ 14 3-(CH₂)₂—N(CH₂CH₂CH₃)₂ 152-(CH₂)₂—N(CH₂CH₂CH₃)₂ 16 4-CH₂—N(CH₂CH₂CH₃)₂ 17 3-CH₂—N(CH₂CH₂CH₃)₂ 182-CH₂—N(CH₂CH₂CH₃)₂ 19 4-O—(CH₂)₂—N(CH₂CH₂CH₃)₂ 204-S—(CH₂)₂—N(CH₂CH₂CH₃)₂ 21 4-O—(CH₂)₂—N(CH₃)₂ 22 4-S—(CH₂)₂—N(CH₃)₂

[Methods for Preparation of the Compounds of the Present Invention]

Hydroxamic acid derivatives of the formula (I) in the present invention,non-toxic salts thereof and prodrugs thereof may be prepared by thefollowing methods or the methods described in examples.

[1] Among the compounds of the present invention, the prodrugs of theformula (IA) may be prepared by the following methods of (a)-(c).

(a) Among the prodrugs of the formula (IA), the compounds in which R¹doesn't represent a group containing amino, thiol and carboxy, that is,the compounds of the formula (IA-a)

(wherein, R^(1-a) has the same meaning as R¹. With the proviso thatR^(1-a) doesn't represent a group containing of amino, thiol and carboxyand the other symbols have the same meaning as defined hereinbefore.)may be prepared by amidation of the compounds of the formula (II)

(wherein, all the symbols have the same meaning as definedhereinbefore.) and the compounds of the formula (III)

H₂N—OR¹⁴  (III)

(wherein, R¹⁴ has the same meaning as defined hereinbefore.).

The amidation is known. For example, it may be carried out

(1) by the method with using acid halide,

(2) by the method with using mixed acid anhydride,

(3) by the method with using conducing agent etc.

Concrete description of these methods are as follows:

(1) The method with acid halide may be carried out, for example;carboxylic acid is reacted with an acid halide (oxalyl chloride orthionyl chloride etc.) in an organic solvent (chloroform, methylenechloride, diethyl ether or tetrahydrofuran etc.) or without solvents atfrom −20° C. to a refluxing temperature to give an acid halide. Theobtained acid halide and an amine are reacted in an organic solvent(chloroform, methylene chloride, diethyl ether or tetrahydrofuran etc.)in the presence of tertiary amine (pyridine, triethylamine,dimethylaniline or dimethylaminopyridine etc.), at 0-40° C. Also thisreaction may be carried out by the reaction with amine and acid halidein an organic solvent (dioxane or tetrahydrofuran etc.), with an aqueousalkali solution (solution of bicarbonate or solution of sodium hydroxideetc.) at 0-40° C.

(2) The method with mixed acid anhydride may be carried out, forexample; carboxylic acid is reacted with an acid halide (pivaloylchloride etc.) or an acid derivative (ethyl chloroformate or isobutylchloroformate etc.) in an organic solvent (chloroform, methylenechloride, diethyl ether or tetrahydrofuran etc.) or without solvents, inthe presence of tertiary amine (pyridine, triethylamine, dimethylanilineor dimethylaminopylidine etc.), at 0-40° C. The mixed acid anhydride isreacted with an amine in an organic solvent (chloroform, methylenechloride, diethyl ether or tetrahydrofuran etc.) at 0-40° C.

(3) The method with condensing agent may be carried out, for example; acarboxylic acid and an amine are reacted in an organic solvent(chloroform, methylene chloride, dimethylformamide, diethyl ether ortetrahydrofuran etc.) or without solvents in the presence or absence oftertiary amine (pyridine, triethylamine, dimethylaniline ordimethylaminopyridine etc.) using with condensing agent(1,3-dicyclohexylcarbodiimido (DCC),1-ethyl-3-[3-(dimethylamino)propyl]carbodiimido (EDC),1,1′-carbonyidiimidazole (CDI), 2-chloro-1-methylpyridinium iodide or1-propanephosphonic acid cyclic anhydride (PPA) etc.) using or without1-hydroxybenzotriazole (HOBt) at 0-40° C.

Preferably, the above reactions (1), (2) and (3) are carried out underan atmosphere of an inert gas (argon, nitrogen etc.) on anhydrouscondition.

(b) Among the prodrugs of the formula (IA), the above compounds of theformula (IA-a) may be prepared by coupling reaction with the compoundsof the formula (IV)

(wherein, X is halogen and the other symbols have the same meaning asdefined hereinbefore.) and the compounds of the formula (V)

(wherein all the symbols have the same meaning as defined hereinbefore.)or the compounds of the formula (VI)

(wherein all the symbols have the same meaning as definedhereinbefore.).

The reaction is known. For example, it may be carried out in an organicsolvent (benzene, dimethylformamide, dioxane, tetrahydrofuran, methanol,acetonitrile, dimethoxyethane or acetone etc.) in the presence of a base(sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine,sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesiumcarbonate, thallium carbonate, tripotassium phosphate, cesium fluoride,barium hydroxide or tetrabutylammonium fluoride etc.) and a catalyst(tetrakis(triphenylphosphine)palladium (Pd(PPh₃)₄),dichlorobis(triphenylphosphine)palladium (PdCl₂(PPh₃)₂), palladiumacetate (Pd(OAc)₂), palladium black,1,1-bis(diphenylphosphinoferrocene)dichloro palladium (PdCl₂(dppf)₂),dichlorodiallylpalladium (PdCl₂(allyl)₂) oriodephenylbis(triphenylphosphine)palladium (PhPdl(PPh₃)₂) etc.) at roomtemperature −120° C.

(c) Among the prodrugs of the formula (IA), the compounds in which R¹ isa group containing at least one of amino, thiol or carboxy, i.e., thecompounds of the formula (IA-c)

(wherein, R^(1-c) is a group containing at least one of amino, thiol orcarboxy and the other symbols have the same meaning as definedhereinbefore.) may be prepared by the removal of a protecting group inthe compounds of the formula (IA-a) in which amino, thiol or carboxy isprotected by a protecting group, i.e., the compounds (IA-a1)

(wherein, R^(1-a1) is a group containing at least one of protectedamino, protected thiol or protected carboxy and the other symbols havethe same meaning as defined hereinbefore.).

A protecting group of amino includes, for example, benzyloxycarbonyl,allyloxycarbonyl, t-butoxycarbonyl, trifluoroacetyl or9-fluorenylmethoxycarbonyl.

A protecting group of thiol includes, for example, benzyl,methoxybenzyl, acetoamidemethyl, triphenylmethyl or acetyl.

A protecting group of carboxy includes, for example, methyl, ethyl,t-butyl, benzyl or allyl.

The protecting group of amino, thiol or carboxy includes the above one,in addition, the other protecting group which is removable selectivelyand easily, for example, one described in T. W. Greene et. al.,Protective Groups in Organic Synthesis, Third Edition,Wiley-Interscience, New York, 1999.

The removal of a protecting group of amino, thiol or carboxy is wellknown. For example, it is

(1) the removal of a protecting group in an alkaline condition,

(2) the removal of a protecting group in an acidic condition,

(3) the removal of a protecting group by hydrogenelysis, or

(4) the removal of a protecting group using metal complex etc.

Concrete description of these methods are as follows:

(1) The removal of protecting group in an alkaline condition may becarried out, for example, in an organic solvent (methanol,tetrahydrofuran or dioxane etc.) with hydroxide of alkaline metal(sodium hydroxide, potassium hydroxide or lithium hydroxide etc.),hydroxide of alkaline earth metal (barium hydroxide or calcium hydroxideetc.), carbonate (sodium carbonate or potassium carbonate etc.), or anaqueous solution thereof or a mixture thereof at 0-40° C.

(2) The removal of protecting group in an acidic condition may becarried out, for example, in an organic solvent (dichloromethane,chloroform, dioxane, ethyl acetate or anisole etc.), organic acid(acetic acid, trifluoroacetic acid or methanesulfonic acid) or inorganicacid (hydrochloric acid or sulfuric acid etc.), or a mixture thereof(hydrogen bromide/acetic acid etc.) at 0-100° C.

(3) The removal of a protecting group by hydrogenelysis may be carriedout, for example, in a solvent (ether (tetrahydrofuran, dioxane,dimethoxyethane or diethylether etc.), alcohol(methanol or ethanoletc.), benzene(benzene or toluene etc.), ketone (acetone ormethylethylketone etc.), nitrile (acetonitrile etc.), amido(dimethylformamide etc.), water, ethyl acetate, acetic acid or a mixturethereof etc.) in the presence of a catalyst (palladium-carbon, palladiumblack, palladium hydroxide, platinum oxide, raney nickel etc.), atatmospheric or reduced pressure under an atmosphere of hydrogen orammonium formate at 0-200° C.

(4) The removal of a protecting group using metal complex may be carriedout, for example, in an organic solvent (dichloromethane,dimethylformamide or tetrahydrofuran etc.) in the presence of a trapreagent (tributyltin hydride or dimedone etc.) and/or an organic acid(acetic acid etc.) with metal complex(tetrakis(triphenylphosphine)palladium(0) complex etc.) at 0-40° C.

As well known to the person in the art, the aimed compounds of presentinvention may be prepared easily by choice of these reaction.

[2] Among the compounds of the present invention, hydroxamic acidderivatives of the formula (I) may be prepared by the method of (d) or(e).

(d) Among hydroxamic acid derivatives of the formula (I), the compoundwherein R¹ doesn't represent a group containing amino, thiol or carboxy,i.e., the compound of the formula (I-d)

(wherein, all the symbols have the same meaning as definedhereinbefore.) may be prepared by the amidation with the compound of theabove formula (II) and hydroxyamine (H₂N—OH).

The amidation may be carried out by the same procedure as describedhereinbefore.

(e) Hydroxamic acid derivatives of the formula (I) may be prepared bythe removal of a protecting group of the compounds of the above formula(IA).

The removal of a protecting group of the hydroxamic acid is known. Forexample, it is

(1) the removal of a protecting group in an alkaline condition,

(2) the removal of a protecting group in an acidic condition, or

(3) the removal of a protecting group by hydrogenelysis etc.

The removal of a protecting group may be carried out by the sameprocedure as described hereinbefore.

The reaction of the removal of a protecting group of hydroxamic acid inthe present invention means an ordinal one which is well known to theperson in the art, for example, the removal of a protecting group in analkaline condition, the removal of a protecting group in an acidiccondition or the removal of a protecting group by hydrogenelysis. Theaimed compounds of the present invention may be prepared easily bychoice of these reaction.

As well known to the person in the art, a protecting group of hydroxamicacid includes, for example, t-butyl, —C(CH₃)₂—OCH₃ and benzyl. Inaddition, such a group includes the other protecting group which isremovable selectively and easily, for example, one described in T. W.Greene et. al., Protective Groups in Organic Synthesis, Third Edition,Wiley-Interscience, New York, 1999.

[3] Among the compounds of the present invention, the prodrugs of theformula (IB) may be prepared by the removal of the methanol in thecompounds of the formula (IA) wherein R¹⁴ is 1-methoxy-1-methylethyl,i.e., the compounds of the formula (IA-3)

(wherein, all the symbols have the same meaning as definedhereinbefore.).

The reaction of the removal of methanol is known. For example, it may becarried out in an organic solvent (benzene, toluene, dioxane or pyridineetc.) at 60-1 50° C.

The compounds of the formula (II) and (IV) are known per se or may beprepared according to the following Reaction Scheme 1 and ReactionScheme 2 or by known methods easily.

In reaction scheme,

R¹⁰¹ is C1-4 alkyl or —CH₂CH₂OCH₂CH₂OCH₃,

R^(1-a), R⁸, R⁹, R¹⁴, ring A, ring B, E, m, n or X have the same meaningas defined hereinbefore.

In above reaction schemes, each reaction may be carried out by eachconventional technique. Further, in above reaction scheme, the compoundsof the formula (X), (XIV), (III), (V) and (VI) used as startingmaterials have been known per se or may be prepared by known methodseasily.

In each reaction in the present specification, obtained products may bepurified by conventional techniques. For example, purification may becarried out by distillation at atmospheric or reduced pressure, by highperformance liquid chromatography, by thin layer chromatography or bycolumn chromatography using silica gel or magnesium silicate, by washingor by recrystallization. Purification may be carried out after eachreaction, or after a series of reactions.

The other starting materials and each test compounds in the presentinvention have been known per se or may be prepared by known methods.

[Pharmacological Activities of the Compounds of the Present Invention]

According to following experiments, it is confirmed that the compound ofthe present invention has an inhibitory activity on IL-6 production.

(1) The Measurement of an Inhibitory Activity on IL-6 Production fromA549 Cells

[Method]

1.5×10⁴ of A549 cells (human lung epithelial cell line) were suspendedin 100 μL of Dulbecco's Modified Eagle Medium (DMEM) containing 0.5%fetal bovine serum (abbreviated as FBS) and incubated for a day andnight in 96 well-microplate. 20 μL of the test compound dissolved indimethylsulfoxide (DMSO) at various concentrations and 80 μL of tumornecrosis factor-α (TNF-α (Genzyme Co., cat. No. TNF-H)) dissolved inserum-free DMEM at the concentration of 12.5 ng/mL were added thereto.After the incubation for 24 hours, the supernatant (100 μL) wascollected to measure the amount of IL-6 being produced using enzymelinked immuno solvent assay (ELISA) (R&D Systems Co., cat. No. D6050).Then the inhibitory activity of the test compound was calculated and the50% inhibitory concentration (IC₅₀) was determined. For example, theIC₅₀ value of the compound of example 3 was 0.052 μM.

(2) The Measurement of an Inhibitory Activity on IL-6 Production fromHuman Synovial Cells

[Method]

3.0×10³ of synovial cells from rheumatoid arthritis patients weresuspended in 200 μL of DMEM containing 10% FBS and incubated for a dayand night in 96 well-microplate, followed by the incubation for 5 hoursin serum-free DMEM. 20 μL of the test compound dissolved in DMSO atvarious concentrations and 80 μL of interleukin-1β (IL-1β (Genzyme Co.,cat. No. 80-3688-01)) dissolved in DMEM containing 2.5% fetal bovineserum at the concentration of 5 ng/mL were added thereto. After theincubation for 24 hours, the supernatant (100 μL) was collected tomeasure the amount of IL-6 being produced using ELISA (R&D Systems Co.,cat. No. D6050). Then the inhibitory activity of the test compound wascalculated and the 50% inhibitory concentration (IC₅₀) was determined.For example, the IC₅₀ value of the compound of example 3 was 0.041 μM.

(3) The Effect on Collagen-induced Arthritis Model in Rats

[Method]

Eight weeks old female DA rats were used. During the experimentalperiod, they were housed in animal room artificially kept the roomtemperature of 24±2° C., humidity of 55±5%, and 12 hours interval oflight and dark cycle. They had free access to a standard solid pelletchow (CE-2, Japan CLEA) and drinking tap water, and were used for theexperiment after a week acclimation. The collagen-induced arthritis wasperformed by the following method. After the mixing of bovine type IIcollagen (0.3% collagen solution, KOKEN #K41, lot. 11214, abbreviated asCII), incomplete Freund's adjuvant (DIFCO #0639-60) and saline with theratio of 1:2:1, the mixture was then ultra-sonicated to form emulsionfor 20 seconds×3 times at 1 minute interval. The intradermal injectionof 0.1 mL of the emulsion (0.75 mg of CII/mL) was performed on each fourdifferent portions of the back on day 0. A week after the firstimmunization, arthritis was elicited by the intradermal injection of0.15 mL of the emulsion at the basal portion of the tail. The testcompound was suspended in 0.5% carboxymethylcellulose solution, and wasadministered orally in the morning and evening twice a day from day 0 today 28. According to the method of Osterman T. et al. (Inflamm. Res.,44, 258-263, 1995), the severity of arthritis was judged and scored. Thehind paw volume of each animal was also measured with the plethysmometer(UNICOM, TK-101CMP). For example, 10 mg/kg/day (b.i.d.) of the compoundof the example 3 completely inhibited the development of arthritis, andthe example 3 even at the dose of 3 mg/kg/day showed significantinhibition by approximately 60% on the arthritis score and the hind pawedema.

[Toxicity]

The toxicity of the compounds of formula (I) of the present invention,nonoxic salts thereof or prodrugs thereof is very low and therefore thecompounds may be considered safe for pharmaceutical use.

[Application for Pharmaceuticals]

The compounds of the present invention possess an inhibitory activity ofIL-6 production in animal, especially human, so they are useful for theprevention and/or treatment of, for example, various inflammatorydiseases, sepsis, multiple myeloma, plasma cell leukemia, osteoporosis,cachexia, psoriasis, nephritis, renal cell carcinoma, Kaposi's sarcoma,rheumatoid arthritis, hypergammaglobulinemia , Castleman's disease,atrial myxoma, diabetes mellitus, autoimmne diseases, hepatitis,colitis, graft versus host disease, infectious diseases andendometriosis.

For the purpose above described, the compounds of formula (I), non-toxicsalts thereof or prodrugs thereof may be normally administeredsystemically or locally, usually by oral or parenteral administration.

The doses to be administered are determined depending upon, for example,age, body weight, symptom, the desired therapeutic effect, the route ofadministration, and the duration of the treatment. In the human adult,the doses per person are generally from 1 mg to 1000 mg, by oraladministration, up to several times per day, and from 0.1 mg to 100 mg,by parenteral administration (preferably intravenous administration), upto several times per day, or continuous administration from 1 to 24hours per day from vein.

As mentioned above, the doses to be used depend upon various conditions.Therefore, there are cases in which doses lower than or greater than theranges specified above may be used.

The compounds of the present invention may be administered in the formof, for example, solid forms for oral administration, liquid forms fororal administration, injections, liniments or suppositories forparenteral administration.

Solid forms for oral administration include compressed tablets, pills,capsules, dispersible powders, and granules. Capsules include hardcapsules and soft capsules.

In such solid forms, one or more of the active compound(s) may beadmixed with vehicles (such as lactose, mannitol, glucose,microcrystalline cellulose, starch), binders (such as hydroxypropylcellulose, polyvinylpyrrolidone or magnesium metasilicate aluminate),disintegrants (such as cellulose calcium glycolate), lubricants (such asmagnesium stearate), stabilizing agents, and solution adjuvants (such asglutamic acid or aspartic acid) and prepared according to methods wellknown in normal pharmaceutical practice. The solid forms may, ifdesired, be coated with coating agents (such as sugar, gelatin,hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), orbe coated with two or more films. And further, coating may includecontainment within capsules of absorbable materials such as gelatin.

Liquid forms for oral administration include pharmaceutically acceptablesolutions, suspensions and emulsions, syrups and elixirs. In such forms,one or more of the active compound(s) may be dissolved, suspended oremulized into diluent(s) commonly used in the art (such as purifiedwater, ethanol or a mixture thereof). Furthermore, such liquid forms mayalso comprise some additives, such as wetting agents, suspending agents,emulsifying agents, sweetening agents, flavoring agents, aroma,preservative or buffering agent.

Injections for parenteral administration include sterile aqueous,suspensions, emulsions and solid forms which are dissolved or suspendedinto solvent(s) for injection immediately before use. In injections, oneor more of the active compound(s) may be dissolved, suspended oremulized into solvent(s). The solvents may include distilled water forinjection, physiological salt solution, vegetable oil, propylene glycol,polyethylene glycol, alcohol, e.g. ethanol, or a mixture thereof.Injections may comprise some additives, such as stabilizing agents,solution adjuvants (such as glutamic acid, aspartic acid orPOLYSORBATE80 (registered trade mark)), suspending agents, emulsifyingagents, soothing agent, buffering agents, preservative. They may besterilized at a final step, or may be prepared and compensated accordingto sterile methods. They may also be manufactured in the form of sterilesolid forms such as freeze-dried products, which may be dissolved insterile water or some other a sterile diluent(s) for injectionimmediately before use.

Other forms for parenteral administration include liquids for externaluse, IL-6 ointments and endermic liniments, inhalations, sprays,suppositories and pessaries for vaginal administration which compriseone or more of the active compound(s) and may be prepared by methodsknown per se.

Sprays may comprise additional substances other than diluents, such asstabilizing agents (such as sodium sulfate), isotonic buffers (such assodium chloride, sodium citrate or citric acid). For preparation of suchsprays, for example, the method described in the U.S. Pat. No. 2,868,691or U.S. Pat. No. 3,095,355 may be used.

THE BEST MODE FOR CARRYING OUT THE INVENTION

The following reference examples and examples are intended to illustratethe present invention, but do not limit them.

In chromatographic separations and TLC, the solvents in parenthesis showthe eluting and developing solvents and the ratios of the solvents usedare by volume.

The solvents in parenthesis in NMR show the solvents used formeasurement.

REFERENCE EXAMPLE 1 Ethyl 6-(4-(4-chlorophenyl)phenyl)-6-oxohexanoate

To adipic acid mono ethyl ester (34.8 g) was added thionyl chloride (72mL). The reaction mixture was stirred at 100° C. for 1.5 hours. Thereaction mixture was concentrated to give adipinyl chloride mono ethylester. To a suspension of aluminium chloride (53.3 g) in dichloromethane(500 mL) was added 4-chlorobiphenyl (37.7 g) at 5° C. The reactionmixture was stirred for 15 minutes and a solution of adipinyl chloridemono ethyl ester in dichloromethane (200 mL) was added thereto at 5° C.The reaction mixture was stirred at room temperature for 2 hours. To thereaction mixture was added ice water and the mixture was extracted withdichloromethane. The extract was washed with water, a saturated aqueoussolution of sodium hydrogen carbonate and a saturated aqueous solutionof sodium chloride, dried over anhydrous magnesium sulfate, andconcentrated. The obtained residue was recrystallized from hexane/ethylacetate and dried to give the title compound (53.8 g) having thefollowing physical data.

TLC: Rf 0.60 (chloroform),

NMR (CDCl₃): δ 8.04 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.56 (d,J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 4.14 (q, J=7.2 Hz, 2H), 3.03 (t,J=6.6 Hz, 2H), 2.38 (t, J=7.0 Hz, 2H), 1.95-1.60 (m, 4H), 1.26 (t, J=7.2Hz, 3H).

REFERENCE EXAMPLE 2 Ethyl6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoate

To a mixture solution of the compound prepared in reference example 1(10.02 g) in dichloromethane (300 mL) and methanol (100 mL) was addedsodium borohydride (5.4 g) at 0° C. The reaction mixture was stirred atroom temperature for 2 hours. The reaction mixture was poured Into asaturated aqueous solution of ammonium chloride and extracted withdichloromethane. The extract was washed with a saturated aqueoussolution of sodium chloride, dried over anhydrous sodium sulfate, andconcentrated to give the title compound (10.03 g) having the followingphysical data.

TLC: Rf 0.25 (chloroform),

NMR (CDCl₃): δ 7.65-7.34 (m, 8H), 4.73 (t, J=6.2 Hz, 1H), 4.11 (q, J=7.0Hz, 2H), 2.03 (t, J=7.0 Hz, 2H), 1.90-1.30 (m, 6H), 1.23 (t, J=7.0 Hz,3H).

REFERENCE EXAMPLE 3 6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoic acid

To a solution of the compound prepared in reference example 2 (10.03 g)in ethanol (100 mL) was added 2N aqueous solution of sodium hydroxide(50 mL). The reaction mixture was stirred at 60° C. for 1 hour. To thereaction mixture was added 1N aqueous solution of hydrochloric acid andthe mixture was extracted with ethyl acetate. The extract was washedwith a saturated aqueous solution of sodium chloride, dried overanhydrous sodium sulfate, and concentrated. The obtained residue wasrecrystallized from isopropylalcohol and dried to give the titlecompound (9.12 g) having the following physical data.

TLC: Rf 0.52 (chloroform:tetrahydrofuran:acetic acid=10:4:1),

NMR (d₆-DMSO): δ 11.80 (brs, 1H), 7.68 (d, J=8 Hz, 2H), 7.61 (d, J=8 Hz,2H), 7.49 (d, J=8 Hz, 2H), 7.40 (d, J=8 Hz, 2H), 5.16 (brs, 1H),4.65-4.40 (m, 1H), 2.18 (t, J=7 Hz, 2H), 1.80-1.05 (m, 6H).

EXAMPLE 1N-(1-methoxy-1-methyl)ethoxy-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide

Under an atmosphere of argon, to a solution of the compound prepared inreference example 3 (7.74 g) in dimethylformamide (150 mL) was added1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide (6.99 g),1-hydroxybenzotriazol (5.58 g), (1-methoxy-1-methylethyl)hydroxyamine(8.0 g) and triethylamine (15.5 mL). The reaction mixture was stirred atroom temperature overnight. The reaction mixture was poured into icewater and extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium hydrogen carbonate and a saturatedaqueous solution of sodium chloride, dried over anhydrous sodiumsulfate, and concentrated. The obtained residue was purified by columnchromatography on silica gel (ethylacetate:hexane:triethylamine=80:20:1) to give the compound of thepresent invention (8.1 g) having the following physical data.

TLC: Rf 0.50 (ethyl acetate:methanol=20:1),

NMR (CDCl₃): δ 7.73 (brs, 1H), 7.60-7.35 (m, 8H), 4.74 (t, J=6 Hz, 1H),3.31 (s, 3H), 2.50-1.15 (m, 8H), 1.41 (s, 6H).

EXAMPLE 2 N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide

To a solution of the compound prepared in example 1 (7.27 g) in methanol(100 mL) was added concentrated hydrochloric acid (2.0 mL). The reactionmixture was stirred at room temperature for 30 minutes. The reactionmixture was concentrated and distilled off an azetropic mixture withethanol. To the obtained residue was added ethyl acetate and theprecipitated crystal was filtered and dried to give the compound of thepresent invention (5.55 g) having the following physical data.

TLC: Rf 0.21 (chloroform:methanol:acetic acid=10:1:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.68 (d, J=8.8 Hz, 2H),7.65 (d, J=8.8 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H),5.15 (d, J=4.4 Hz, 1H), 4.54 (m, 1H), 1.93 (t, J=7.3 Hz, 2H), 1.70-1.40(m, 4H), 1.40-1.10 (m, 2H).

EXAMPLES 2(1)-2(5)

By the same procedure as a series of reactions of reference example1→reference example 2→reference example 3→example 1→example 2 using acorresponding benzene derivative instead of 4-chlorobiphenyl, thefollowing compounds of the present invention were obtained.

EXAMPLE 2(1) N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide

TLC: Rf 0.42 (ethyl acetate:methanol=39:1),

NMR (d₆-DMSO): δ 10.29 (brs, 1H), 8.64 (brs, 1H), 7.66-7.58 (m, 4H),7.47-7.30 (m, 5H), 5.18-5.09 (m, 1H), 4.57-4.55 (m, 1H), 1.91 (t, J=7.5Hz, 2H), 1.64-1.44 (m, 4H), 1.40-1.20 (m, 2H).

EXAMPLE 2(2) N-hydroxy-4-(4-cyclohexylphenyl)-6-hydroxyhexanamide

TLC: Rf 0.32 (ethyl acetate),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.19 (d, J=7.8 Hz, 2H),7.12 (d, J=7.8 Hz, 2H), 4.98 (d, J=4.5 Hz, 1H), 4.40-4.38 (m, 1H),2.48-2.40 (m, 1H), 1.89 (t, J=7.5 Hz, 2H), 1.81-1.12 (m, 16H).

EXAMPLE 2(3) N-hydroxy-6-(4-(4-methylphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.43 (ethyl acetate),

NMR (d₆-DMSO): δ 10.29 (brs, 1H), 8.62 (d, J=1.5 Hz, 1H), 7.56 (d, J=8.4Hz, 2H), 7.53 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.25 (d, J=8.4Hz, 2H), 5.11 (d, J=4.5 Hz, 1H), 4.54-4.48 (m, 1H), 2.33 (s, 3H), 1.91(t, J=7.5 Hz, 2H), 1.63-1.16 (m, 6H).

EXAMPLE 2(4) N-hydroxy-6-(4-(4-methoxyphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.27 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.29 (brs, 1H), 8.63 (d, J=1.5 Hz, 1H), 7.57 (d, J=8.1Hz, 2H), 7.53 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 7.00 (d, J=8.1Hz, 2H), 5.10 (d, J=4.5 Hz, 1H), 4.53-4.47 (m, 1H), 3.78 (s, 3H), 1.91(t, J=7.2 Hz, 2H), 1.66-1.15 (m, 6H).

EXAMPLE 2(5)N-hydroxy-6-(4-(trans-4-propylcycrohexyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.16 (ethyl acetate),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.20 (d, J=8.5 Hz, 2H),7.13 (d, J=8.5 Hz, 2H), 4.98 (d, J=4.4 Hz, 1H), 4.43 (m, 1H), 2.41 (m,1H), 2.00-0.90 (m, 21H), 0.88 (t, J=7.0 Hz, 3H).

REFERENCE EXAMPLE 4 Ethyl(R)-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoate

To a solution of the compound prepared in reference example 1 (17.2 g)in tetrahydrofuran (1500 mL) was added a solution of 1.0M(S)-2-methyloxazaborolidine in toluene (5 mL) at room temperature. Thereaction mixture was cooled to −15° C. and a solution of 2.0Mborane-dimethylsulfide complex in tetrahydrofuran (21.3 mL) was addedthereto. The reaction mixture was stirred at room temperature for 3hours. To the reaction mixture was added methanol and the mixture wasstirred over night. The reaction mixture was concentrated, diluted withethyl acetate, washed with water and a saturated aqueous solution ofsodium chloride, dried over magnesium sulfate, and concentrated. Theobtained residue was purified by column chromatography on silica gel(hexane:ethyl acetate=1:1) to give the title compound (17 g, 94.2% e.e.,HPLC) having the following physical data.

TLC: Rf 0.25 (chloroform),

HPLC: 13.7 min (retention time), Column: DAICEL CHIRAL CELAD-RH, 4.6×150mm; Eluant: acetonitrile:water=75:25; UV: 260 nm; Flow rate: 1.0 mL/min.

REFERENCE EXAMPLE 5 Ethyl(S)-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanoate

By the same procedure as a series of reactions of reference example 4using a solution of 1.0M (R)-2-methyl-oxazaborolidine in toluene insteadof a solution of 1.0M (S)-2-methyl-oxazaborolidine in toluene, the titlecompound (91% e.e., HPLC) having the following physical data wasobtained.

TLC: Rf 0.25 (chloroform),

HPLC: 9.8 min (retention time), Column: DAICEL CHIRAL CELAD-RH, 4.6×150mm; Eluant: acetonitrile:water=75:25; UV: 260 nm; Flow rate: 1.0 mL/min.

EXAMPLE 3(R)-(+)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example3→example 1→example 2 using the compound prepared in reference example 4instead of the compound prepared in reference example 2, the compound ofthe present invention (98.7% e.e., HPLC) having the following physicaldata was obtained.

TLC: Rf 0.21 (chloroform:methanol:acetic acid=10:1:1),

[α]_(D): +9.27 (c 0.280, methanol),

HPLC: 16.8 min (retention time), Column: DAICEL CHIRAL CEL AD-RH,4.6×150 mm; Eluant: acetonitrile:water=35:65; UV: 260 nm; Flow rate: 1.0mL/min.

EXAMPLE 3(1)(S)-(−)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 3 using thecompound prepared in reference example 5 instead of the compoundprepared in reference example 4, the compound of the present invention(>98% e.e., HPLC) having the following physical data was obtained.

TLC: Rf 0.21 (chloroform:methanol:acetic acid=10:1:1),

[α]_(D): −9.60 (c 0.265, methanol),

HPLC: 11.6 min (retention time), Column: DAICEL CHIRAL CEL AD-RH,4.6×150 mm; Eluant: acetonitrile:water=35:65; UV: 260 nm; Flow rate: 1.0mL/min.

REFERENCE EXAMPLE 6N-(1-methoxy-1-methyl)ethoxy-6-(4-iodophenyl)-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example1→reference example 2→reference example 3→example 1 using iodobenzeneinstead of 4-chlorobiphenyl, the title compound having the followingphysical data was obtained.

TLC: Rf 0.40 (ethyl acetate),

NMR (CDCl₃): δ 7.69-7.63 (m, 3H), 7.08 (d, J=8.2 Hz, 2H), 4.64 (t, J=6.2Hz, 1H), 3.31 (s, 3H), 2.42-1.21 (m, 8H), 1.41 (s, 6H).

EXAMPLE 4N-(1-methoxy-1-methyl)ethoxy-6-(4-(benzofuran-2-yl)phenyl)-4-hydroxyhexanamide

To a solution of the compound prepared in reference example 6 (440 mg)in dimethylformamide (1 0 mL) was added tri-potassium phosphate (333mg), tetrakis(triphenylphosphine)palladium (120 mg) andbenzofuran-2-boronic acid (400 mg). The reaction mixture was stirred at60° C. for 2 hours. To the reaction mixture was added water and themixture was extracted with ethyl acetate. The extract was washed with asaturated aqueous solution of sodium chloride, dried over sodium sulfateand concentrated. The obtained residue was purified by columnchromatography on silica gel (ethyl acetate: hexane=1:1→7:3→1:0) to givethe compound of the present invention (178 mg) having the followingphysical data.

TLC: Rf 0.39 (ethyl acetate).

EXAMPLE 5 N-hydroxy-6-(4-(benzofuran-2-yl)phenyl)-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 2 using thecompound prepared in example 4 instead of the compound prepared inexample 1, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.29 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 7.85 (d, J=8.1 Hz, 2H), 7.65-7.59 (m,2H), 7.42 (d, J=8.1 Hz, 2H), 7.37 (s, 1H), 7.32-7.21 (m, 2H), 4.58-4.51(m, 1H), 1.90 (t, J=7.2 Hz, 2H), 1.62-1.14 (m, 6H).

EXAMPLES 5(1)-5(18)

By the same procedure as a series of reactions of example 4→example 5using a corresponding boronic acid instead of benzofuran-2-boronic acid,the following compounds of the present invention were obtained.

EXAMPLE 5(1) N-hydroxy-6-(4-(pyridin-4-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.33 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.63 (s, 1H), 8.61 (dd, J=4.8 Hz, 1.5Hz, 2H), 7.74 (d, J=8.1 Hz, 2H), 7.68 (dd, J=4.8 Hz, 1.5 Hz, 2H), 7.44(d, J=8.1 Hz, 2H), 5.21 (d, J=4.5 Hz, 1H), 4.58-4.52 (m, 1H), 1.91 (t,J=7.2 Hz, 2H), 1.64-1.14 (m, 6H).

EXAMPLE 5(2) N-hydroxy-6-(4-(pyridin-3-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.34 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.86 (d, J=1.8 Hz, 1H), 8.62 (s, 1H),8.54 (dd, J=4.8 Hz, 1.8 Hz, 1H), 8.06-8.02 (m, 1H), 7.65 (d, J=8.1 Hz,2H), 7.48-7.43 (m, 1H), 7.42 (d, J=8.1 Hz, 2H), 5.17 (d, J=4.5 Hz, 1H),4.56-4.50 (m, 1H), 1.90 (t, J=7.5 Hz, 2H), 1.63-1.18 (m, 6H).

EXAMPLE 5(3) N-hydroxy-6-(4-(2-chlorophenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.25 (ethyl acetate),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.55-7.52 (m, 1H),7.40-7.33 (m, 7H), 5.16 (d, J=4.5 Hz, 1H), 4.54-4.51 (m, 1H), 1.91 (t,J=6.9 Hz, 2H), 1.65-1.20 (m, 6H).

EXAMPLE 5(4) N-hydroxy-6-(4-(3-chlorophenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.23 (ethyl acetate),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.68 (t, J=1.8 Hz, 1H),7.63-7.60 (m, 3H), 7.46 (t, J=8.1 Hz, 1H), 7.40-7.37 (m, 3H), 5.16 (d,J=4.2 Hz, 1H), 4.54-4.50 (m, 1H), 1.90 (t, J=7.2 Hz, 2H), 1.63-1.20 (m,6H).

EXAMPLE 5(5) N-hydroxy-6-(4-(4-bromophenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.35 (ethyl acetate:methanol=9:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.70-7.50 (m, 6H), 7.40(d, J=8.4 Hz, 2H), 5.15 (d, J=4.5 Hz, 1H), 4.54 (m, 1H), 1.93 (t, J=7.2Hz, 2H), 1.70-1.20 (m, 6H).

EXAMPLE 5(6) N-hydroxy-6-(4-(thiophen-2-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.26 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (brs, 1H), 7.57 (d, J=8.7 Hz, 2H),7.49 (dd, J=5.1 Hz, 1.2 Hz, 1H), 7.45 (dd, J=3.6 Hz, 1.2 Hz, 1H), 7.32(d, J=8.7 Hz, 2H), 7.10 (dd, J=5.1 Hz, 3.6 Hz, 1H), 5.13 (d, J=4.5 Hz,1H), 4.51-4.45 (m, 1H), 1.89 (t, J=6.9 Hz, 2H), 1.60-1.15 (m, 6H).

EXAMPLE 5(7) N-hydroxy-6-(4-(furan-2-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.27 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (brs, 1H), 8.65 (brs, 1H), 7.70 (d, J=2.1 Hz,1H), 7.62 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 6.87 (d, J=3.6 Hz,1H), 6.56 (dd, J=3.6 Hz, 2.1 Hz, 1H), 5.13 (d, J=4.5 Hz, 1H), 4.50-4.45(m, 1H), 1.89 (t, J=7.2 Hz, 2H), 1.60-1.12 (m, 6H).

EXAMPLE 5(8)N-hydroxy-6-(4-(1,3-dioxy-2,3-dihydroinden-5-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.22 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (brs, 1H), 7.51 (d, J=8.1 Hz, 2H),7.32 (d, J=8.1 Hz, 2H), 7.21 (d, J=1.8 Hz, 1H), 7.10 (dd, J=8.1 Hz, 1.8Hz, 1H), 6.96 (d, J=8.1 Hz, 1H), 6.03 (s, 2H), 5.10 (d, J=4.5 Hz, 1H),4.52-4.47 (m, 1H), 1.90 (t, J=7.2 Hz, 2H), 1.60-1.12 (m, 6H).

EXAMPLE 5(9)N-hydroxy-6-(4-(4-methylthiophenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.27 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (brs, 1H), 7.59 (d, J=8.4 Hz, 2H),7.57 (d, J=8.4 Hz, 2H), 7.36 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H),5.12 (d, J=4.2 Hz, 1H), 4.53-4.48 (m, 1H), 3.30 (s, 3H), 1.90 (t, J=7.2Hz, 2H), 1.62-1.16 (m, 6H).

EXAMPLE 5(10)N-hydroxy-4-(4-(naphthalen-1-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.30 (ethyl acetate),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.99-7.91 (m, 2H), 7.80(d, J=8.1 Hz, 1H), 7.58-7.39 (m, 8H), 5.19 (d, J=4.5 Hz, 1H), 4.61-4.55(m, 1H), 1.94 (t, J=7.5 Hz, 2H), 1.68-1.23 (m, 6H).

EXAMPLE 5(11)N-hydroxy-6-(4-(naphthalen-2-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.27 (ethyl acetate),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 7.99-7.90(m, 3H), 7.83 (dd, J=8.1 Hz, 1.5 Hz, 1H), 7.75 (d, J=8.1 Hz, 2H),7.55-7.47 (m, 2H), 7.43 (d, J=8.1 Hz, 2H), 5.16 (d, J=4.2 Hz, 1H),4.60-4.51 (m, 1H), 1.91 (t, J=7.2 Hz, 2H), 1.66-1.20 (m, 6H).

EXAMPLE 5(12) N-hydroxy-6-(4-(4-acetylphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.19 (chloroform:methanol:triethylamine=8:1:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.64 (s, 1H), 8.03 (d, J=8.4 Hz, 2H),7.82 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H),5.18 (d, J=4.5 Hz, 1H), 4.56 (m, 1H), 2.61 (s, 3H), 1.92 (t, J=7.8 Hz,2H), 1.70-1.42 (m, 4H), 1.42-1.18 (m, 2H).

EXAMPLE 5(13)N-hydroxy-6-(4-(4-hydroxyphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.23 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 9.47 (s, 1H), 8.62 (s, 1H), 7.48 (d,J=8.4 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 6.81 (d,J=8.7 Hz, 2H), 5.07 (d, J=4.2 Hz, 1H), 4.51-4.45 (m, 1H), 1.90 (t, J=7.2Hz, 2H), 1.62-1.17 (m, 6H).

EXAMPLE 5(14)N-hydroxy-6-(4-(dibenzofuran-4-yl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.29 (ethyl acetate),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.63 (s, 1H), 8.18 (d, J=7.2 Hz, 1H),8.13 (dd, J=7.5 Hz, 1.2 Hz, 1H), 7.84 (d, J=8.1 Hz, 2H), 7.73 (d, J=7.2Hz, 1H), 7.67 (dd, J=7.5 Hz, 1.2 Hz, 1H), 7.56-7.39 (m, 5H), 5.19 (d,J=4.2 Hz, 1H), 4.60-4.55 (m, 1H), 1.93 (t, J=7.2 Hz, 2H), 1.66-1.21 (m,6H).

EXAMPLE 5(15)N-hydroxy-6-(4-(2-methoxyphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.65 (s, 1H), 7.40 (d, J=8.4 Hz, 2H),7.36-7.23 (m, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.4 Hz, 1H), 7.02(t, J=7.5 Hz, 1H), 5.11 (d, J=4.5 Hz, 1H), 4.51 (m, 1H), 3.76 (s, 3H),1.93 (t, J=7.2 Hz, 2H), 1.68-1.15 (m, 6H).

EXAMPLE 5(16)N-hydroxy-6-(4-(3-methoxyphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.60 (d, J=8.1 Hz, 2H),7.38 (d, J=8.1 Hz, 2H), 7.36 (t, J=8.1 Hz, 1H), 7.23-7.13 (m, 2H),6.95-6.87 (m, 1H), 5.14 (d, J=4.2 Hz, 1H), 4.53 (m, 1H), 3.80 (s, 3H),1.92 (t, J=7.2 Hz, 2H), 1.70-1.15 (m, 6H).

EXAMPLE 5(17)N-hydroxy-6-(4-(4-trifluoromethylphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.65 (s, 1H), 7.89 (d, J=8.7 Hz, 2H),7.80 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H),5.20 (d, J=4.2 Hz, 1H), 4.56 (m, 1H), 1.93 (t, J=7.5 Hz, 2H), 1.70-1.15(m, 6H).

EXAMPLE 5(18)N-hydroxy-6-(4-(4-t-butylphenyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.20 (chloroform:methanol:triethylamine=8:1:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.64 (s, 1H), 7.57 (d, J=8.4 Hz, 4H),7.46 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 5.13 (d, J=4.2 Hz, 1H),4.52 (m, 1H), 1.92 (t, J=7.2 Hz, 2H), 1.65-1.20 (m, 6H), 1.31 (s, 9H).

REFERENCE EXAMPLE 7 2-(2-methoxyethoxy)ethyl6-(4-bromophenyl)-6-oxohexanoate

To a solution of 6-(4-bromophenyl)-6-oxohexanoic acid (52 g) indichloromethane (200 mL) was added oxalyl chloride (32 mL). The reactionmixture was stirred at 40° C. for 3 hours. The reaction mixture wasconcentrated. A solution of the obtained residue in toluene (500 mL) wasdropped to di(ethylene glycol)methyl ether (65 mL) at 0° C. The reactionmixture was stirred at room temperature overnight and triethylamine (25mL) was dropped thereto at room temperature. The reaction mixture wasstirred at room temperature for 1 hour. The reaction mixture was pouredinto water and extracted with ethyl acetate. The extract was washed withwater and a saturated aqueous solution of sodium chloride, dried overanhydrous magnesium sulfate and concentrated. To the obtained residuewas added methanol and the precipitate was filtrated. The filtrate wasconcentrated to give the title compound (88 g) having the followingphysical data.

TLC: Rf 0.43 (hexane:ethyl acetate=2:3),

NMR (CDCl₃): δ 7.81 (d, J=8.7 Hz, 2H), 7.60 (d, J=8.7 Hz, 2H), 4.24 (t,J=4.8 Hz, 2H), 3.69 (t, J=4.8 Hz, 2H), 3.66-3.62 (m, 2H), 3.56-3.53 (m,2H), 3.38 (s, 3H), 2.95 (t, J=7.2 Hz, 2H), 2.40 (t, J=7.2 Hz, 2H),1.83-1.67 (m, 4H).

REFERENCE EXAMPLE 8 2-(2-methoxyethoxy)ethyl6-[4-(N-(2-hydroxy-5-methylphenyl)carbamoyl)phenyl]-6-oxohexanoate

Under an atmosphere of argon, to a solution of compound prepared inreference example 7 (75 g) in dimethylacetamide (300 mL) was added4-methyl-2-aminophenol (17.9 g),dichlorobis(triphenylphosphine)palladium(II) (2.78 g),triphenylphosphine (2.07 g), 1,8-diazabicyclo[5.4.0]undec-7-ene (23.7mL). The atmosphere of argon was replaced with carbon monoxide. Thereaction mixture was stirred at 150° C. for 2.5 hours. The reactionmixture was poured into water and extracted with ethyl acetate. Theextract was washed with 1N hydrochloric acid water and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was washed with diethylether to give the title compound (51.3 g) having the following physicaldata.

TLC: Rf 0.27 (hexane:ethyl acetate=1:2),

NMR (CDCl₃): δ 8.29 (brs, 1H), 8.04 (d, J=8.7 Hz, 2H), 8.00-7.98 (m,1H), 7.97 (d, J=8.7 Hz, 2H), 7.19 (s, 1H), 6.98-6.93 (m, 2H), 4.24 (t,J=5.0 Hz, 2H), 3.70 (t, J=5.0 Hz, 2H), 3.66-3.63 (m, 2H), 3.56-3.53 (m,2H), 3.37 (s, 3H), 3.02 (t, J=6.9 Hz, 2H), 2.40 (t, J=6.9 Hz, 2H), 2.29(s, 3H), 1.86-1.68 (m, 4H).

REFERENCE EXAMPLE 9 2-(2-methoxyethoxy)ethyl6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-oxohexanoate

To a suspension of the compound prepared in reference example 8 (49 g)in toluene (500 mL) was added camphor sulfonic acid (24.9 g). Thereaction mixture was stirred at 150° C. for 3.5 hours with dehydratingwith Dean-Stark. The reaction mixture was poured into ice water andextracted with ethyl acetate. The extract was washed with a saturatedaqueous solution of sodium hydrogen carbonate, water and a saturatedaqueous solution of sodium chloride, dried over anhydrous magnesiumsulfate and concentrated. The obtained residue was purified by columnchromatography on silica gel (dichloromethane:ethyl acetate=10:1˜1:1) togive the title compound (33.1 g) having the following physical data.

TLC: Rf 0.42 (hexane:ethyl acetate=1:2),

NMR (CDCl₃): δ 8.33 (d, J=8.7 Hz, 2H), 8.08 (d, J=8.7 Hz, 2H), 7.58 (d,J=1.5 Hz, 1H), 7.48 (d, J=8.1 Hz, 1H), 7.20 (dd, J=8.1, 1.5 Hz, 1H),4.25 (t, J=4.8 Hz, 2H), 3.70 (t, J=4.8 Hz, 2H), 3.66-3.62 (m, 2H),3.57-3.53 (m, 2H), 3.38 (s, 3H), 3.05 (t, J=7.0 Hz, 2H), 2.50 (s, 3H),2.42 (t, J=7.0 Hz, 2H), 1.87-1.70 (m, 4H).

REFERENCE EXAMPLE 9(1) 2-(2-methoxyethoxy)ethyl6-[4-(benzoxazol-2-yl)phenyl]-6-oxohexanoate

By the same procedure as a series of reactions of reference example8→reference example 9 using 2-aminophenol instead of4-methyl-2-aminophenol, the title compound having the following physicaldata were obtained.

TLC: Rf 0.45 (hexane:ethyl acetate=2:3),

NMR (CDCl₃): δ 8.35,(d, J=8.8 Hz, 2H), 8.09 (d, J=8.8 Hz, 2H), 7.85-7.77(m, 1H), 7.67-7.58 (m, 1H), 7.45-7.37 (m, 2H), 4.24 (t, J=4.8 Hz, 2H),3.72 (t, J=4.8 Hz, 2H), 3.67-3.62 (m, 2H), 3.58-3.53 (m, 2H), 3.38 (s,3H), 3.05 (t, J=7.0 Hz, 2H), 2.42 (t, J=7.0 Hz, 2H), 1.90-1.70 (m, 4H).

REFERENCE EXAMPLE 10 2-(2-methoxyethoxy)ethyl6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-oxohexanoate

Under an atmosphere of argon, to a mixture solution of the compoundprepared in reference example 7 (80 g) in dimethylformamide (310 mL) andtriethylamine (155 mL) was added 1-ethynyl-4-methylthiobenzene (27.5 g)and dichlorobis(triphenylphosphine)palladium(II) (10.9 g). The reactionmixture was stirred at 50° C. for 3 hours. The reaction mixture waspoured into an aqueous solution of 2N hydrochloric acid cooled with iceand extracted with ethyl acetate. The extract was washed with 2Nhydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, driedover anhydrous magnesium sulfate and concentrated. The obtained residuewas purified by column chromatography on silica gel (hexane:ethylacetate=2:1˜2:3→chloroform:methanol=20:1) to give the title compound(41.1 g) having the following physical data.

TLC: Rf 0.21 (hexane:ethyl acetate=2:1),

NMR (CDCl₃): δ 7.93 (d, J=8.6 Hz, 2H), 7.59 (d, J=8.6 Hz, 2H), 7.46 (d,J=8.6 Hz, 2H), 7.22 (d, J=8.6 Hz, 2H), 4.28-4.20 (m, 2H), 3.75-3.60 (m,4H), 3.60-3.50 (m, 2H), 3.38 (s, 3H), 2.99 (t, J=7.0 Hz, 2H), 2.51 (s,3H), 2.41 (t, J=7.0 Hz, 2H), 1.85-1.65 (m, 4H).

REFERENCE EXAMPLE 11 2-(2-methoxyethoxy)ethyl6-[4-(4-methylthiophenyl)phenyl]-6-oxohexanoate

By the same procedure as a series of reactons of example 4 using thecompound prepared in reference example 7 and 4-methylthiophenylboronicacid, the title compound having the following physical data wasobtained.

TLC: Rf 0.24 (hexane:ethyl acetate=1:1),

NMR (CDCl₃): δ 8.01 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.7 Hz, 2H), 7.56 (d,J=8.4 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 4.25 (t, J=4.8 Hz, 2H), 3.70 (t,J=4.8 Hz, 2H), 3.66-3.63 (m, 2H), 3.56-3.53 (m, 2H), 3.38 (s, 3H), 3.01(t, J=6.9 Hz, 2H), 2.53 (s, 3H), 2.41 (t, J=6.9 Hz, 2H), 1.86-1.70 (m,4H).

REFERENCE EXAMPLE 12 Methyl6-[4-(4-methylthiophenyl)phenyl]-6-oxohexanoate

By the same procedure as a series of reactions of reference example 1using monomethyl adipate and 4-(N,N-dimethylamino)methylbiphenyl, thetitle compound having the following physical data was obtained.

TLC: Rf 0.51 (dichloromethane:methanol=4:1),

NMR (CDCl₃): δ 8.01 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 7.59 (d,J=8.3 Hz, 2H), 7.42 (d, J=8.3 Hz, 2H), 3.67 (s, 3H), 3.50 (s, 2H), 3.02(t, J=7.0 Hz, 2H), 2.39 (t, J=7.0 Hz, 2H), 2.29 (s, 6H), 1.86-1.70 (m,4H).

EXAMPLE 6(R)-(+)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(5-methylbenzoxaiol-2-yl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example4→reference example 3→example 1 using the compound prepared in referenceexample 9, the compound of the present invention having the followingphysical data was obtained.

[α]_(D): +22.46 (c 0.615, dimethylformamide),

TLC: Rf 0.34 (ethyl acetate),

NMR (CDCl₃): δ 8.19 (d, J=8.1 Hz, 2H), 7.84 (brs, 1H), 7.54-7.53 (m,1H), 7.47 (d, J=8.1 Hz, 2H), 7.44 (d, J=8.1 Hz, 1H), 7.16-7.13 (m, 1H),4.80-4.75 (m, 1H), 3.30 (s, 3H), 2.48 (s, 3H), 2.42-2.08 (m, 2H),1.94-1.32 (m, 6H), 1.41 (s, 6H).

EXAMPLES 6(1)-6(4)

By the same procedure as a series of reactions of example 6 using thecompound prepared in reference example 9(1), 10, 11 or 12 instead of thecompound prepared in reference example 9, the compounds of the presentinvention having the following physical data were obtained.

EXAMPLE 6(1)(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.50 (chloroform:methanol:acetic acid=90:10:1),

NMR (CDCl₃): δ 8.22 (d, J=8.2 Hz, 2H), 7.83 (br, 1H), 7.75 (m, 1H), 7.59(m, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.35 (m, 2H), 4.76 (t, J=6.5 Hz, 1H),3.30 (s, 3H), 2.45-2.12 (m, 2H), 1.85-1.62 (m, 4H), 1.53-1.38 (m, 2H),1.41 (s, 6H).

EXAMPLE 6(2)(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.41 (chloroform:methanol:acetic acid=90:10:1),

NMR (CDCl₃): δ 7.86 (br, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz,2H), 7.30 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 4.68 (t-like, J=6.0Hz, 1H), 3.31 (s, 3H), 2.49 (s, 3H), 2.40-2.10 (m, 2H), 1.82-1.65 (m,4H), 1.50-1.35 (m, 2H), 1.41 (s, 6H).

EXAMPLE 6(3)(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.44 (ethyl acetate),

NMR (CDCl₃): δ 7.79 (br, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.5 Hz,2H), 7.38 (d, J=8.5 Hz, 2H), 7.31 (d, J=8.5 Hz, 2H), 4.71 (t, J=6.0 Hz,1H), 3.30 (s, 3H), 2.52 (s, 3H), 2.43-2.08 (m, 2H), 1.90-1.65 (m, 5H),1.57-1.36 (m, 1H), 1.41 (s, 6H).

EXAMPLE 6(4)(R)-(+)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide

[α]_(D): +22.6 (c 1.04, dimethylformamide),

TLC: Rf 0.17 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 7.58 (d, J=8.1 Hz, 2H), 7.57 (d, J=8.1 Hz, 2H), 7.36(d, J=8.1 Hz, 2H), 7.34 (d, J=8.1 Hz, 2H), 5.12 (d, J=4.5 Hz, 1H), 4.52(m, 1H), 3.39 (s, 2H), 3.18 (s, 3H), 2.14 (s, 6H), 1.98 (t, J=7.2 Hz,2H), 1.65-1.54 (m, 2H), 1.49 (m, 2H), 1.40-1.18 (m, 2H), 1.24 (s, 6H).

EXAMPLE 7(R)-(+)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 2 using thecompound prepared in example 6, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.28 (chloroform:methanol=9:1),

m.p.: 178-179° C.,

[α]_(D): +31.0 (c 1.05, dimethylformamide),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.63 (s, 1H), 8.12 (d, J=8.4 Hz, 2H),7.63 (d, J=8.4 Hz, 1H), 7.57 (m, 1H), 7.53 (d, J=8.4 Hz, 2H), 7.22 (m,1H), 5.31 (d, J=4.2 Hz, 1H), 4.59 (m, 1H), 2.43 (s, 3H), 1.91 (t, J=7.2Hz, 2H), 1.65-1.56 (m, 2H), 1.54-1.45 (m, 2H), 1.41-1.18 (m, 2H).

EXAMPLES 7(1)˜7(4)

By the same procedure as a series of reactions of example 7 using thecompound prepared in example 6(1)-(4) instead of the compound preparedin example 6, if desired, the conversion into the acid addition salts byconventional means, the following compounds of the present inventionwere obtained.

EXAMPLE 7(1)(R)-(+)-N-hydroxy-6-[4-benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.20 (chloroform:methanol:acetic acid=90:10:1),

m.p.: 160˜161° C.,

[α]_(D): +10.10 (c 0.81, methanol),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.64 (s, 1H), 8.14 (d, J=8.2 Hz, 2H),7.82-7.72 (m, 2H), 7.54 (d, J=8.2 Hz, 2H), 7.47-7.34 (m, 2H), 5.32 (d,J=4.4 Hz, 1H), 4.64-4.57 (m, 1H), 1.92 (t, J=7.0 Hz, 2H), 1.70-1.10 (m,6H).

EXAMPLE 7(2)(R)-(+)-N-hydroxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.43 (chloroform:methanol:acetic acid=60:10:1),

m.p.: 173˜176° C.,

[α]_(D): +31.5 (c 1.02, dimethylformamide),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.62 (s, 1H), 7.48 (d, J=8.0 Hz, 2H),7.47 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H),5.22 (d, J=4.4 Hz, 1H), 4.60-4.45 (m, 1H), 2.51 (s, 3H), 1.92 (t, J=7.2Hz, 2H), 1.70-1.10 (m, 6H).

EXAMPLE 7(3)(R)-(+)-N-hydroxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.23 (chloroform:methanol=9:1),

m.p.: 194˜197° C.,

[α]_(D): +6.86 (c 0.105, methanol),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.62 (s, 1H), 7.61-7.55 (m, 4H),7.38-7.29 (m, 4H), 5.12 (d, J=4.4 Hz, 1H), 4.58-4.42 (m, 1H), 2.49 (s,3H), 1.90 (t, J=7.4 Hz, 2H), 1.66-1.02 (m, 6H).

EXAMPLE 7(4)(R)-(+)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

TLC: Rf 0.14 (chloroform:methanol=2:1),

m.p.: 214˜217° C.,

[α]_(D): +26.54 (c 0.11, methanol),

NMR (d₆-DMSO): δ 10.79 (s, 1H), 10.33 (s, 1H), 8.63 (s, 1H), 7.73 (d,J=8.2 Hz, 2H), 7.64-7.62 (m, 4H), 7.39 (d, J=8.2 Hz, 2H), 5.17 (d, J=3.9Hz, 1H), 4.58-4.49 (m, 1H), 4.27 (s, 2H), 2.68 (s, 6H), 1.91 (t, J=6.9Hz, 2H), 1.64-1.18 (m, 2H).

EXAMPLES 8(1)˜8(4)

By the same procedure as a series of reactions of reference example1→reference example 2→reference example 3→example 1→example 2 using acorresponding compound instead of 4-chlorobiphenyl, the followingcompounds of the present invention were obtained.

EXAMPLE 8(1)N-hydroxy-6-(4-(trans-4-butylcyclohexyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 018 (ethyl acetate),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.63 (s, 1H), 7.20 (d, J=8.2 Hz, 2H),7.13 (d, J=8.2 Hz, 2H), 4.99 (d, J=3.9 Hz, 1H), 4.42 (m, 1H), 2.40 (m,1H), 1.91 (t, J=7.2 Hz, 2H), 1.90-0.90 (m, 21H), 0.85 (t, J=6.9 Hz, 3H).

EXAMPLE 8(2)N-hydroxy-6-(4-(trans-4-hydroxycyclohexyl)phenyl)-6-hydroxyhexanamide

TLC: Rf 0.12 (chloroform:methanol:triethylamine=8:1:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.64 (s, 1H), 7.19 (d, J=8.1 Hz, 2H),7.13 (d, J=8.1 Hz, 2H), 4.99 (d, J=4.5 Hz, 1H), 4.54 (d, J=4.5 Hz, 1H),4.42 (q, J=4.5 Hz, 1H), 3.52-3.36 (m, 1H), 2.60-2.30 (m, 1H), 1.95-1.83(m, 4H), 1.80-1.65 (m, 2H), 1.63-1.10 (m, 10H).

EXAMPLE 8(3) N-hydroxy-6-(4-cyclopentylphenyl)-6-hydroxyhexanamide

TLC: Rf 0.18 (chloroform:methanol:triethylamine=8:1:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.64 (s, 1H), 7.20 (d, J=8.4 Hz, 2H),7.16 (d, J=8.4 Hz, 2H), 5.00 (d, J=3.9 Hz, 1H), 4.43 (q, J=3.9 Hz, 1H),3.00-2.85 (m, 1H), 2.06-1.84 (m, 4H), 1.83-1.38 (m, 10H), 1.38-1.10 (m.2H).

EXAMPLE 8(4) N-hydroxy-6-[4-(morpholin-4-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.20 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.27 (s, 1H), 8.61 (s, 1H), 7.14 (d, J=8.7 Hz, 2H),6.85 (d, J=8.7 Hz, 2H), 4.80 (d, J=4.2 Hz, 1H), 4.40-4.35 (m, 1H),3.72-3.69 (m, 4H), 3.05-3.02 (m, 4H), 1.88 (t, J=7.5 Hz, 2H), 1.62-1 .07(m, 6H).

EXAMPLE 9 N-hydroxy-6-[3-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 4→referenceexample 2→reference example 3→example 1→example 2 using methyl6-(3-bromophenyl)-6-oxohexanoate instead of the compound prepared inreference example 6, the compound of the present invention having thefollowing physical data was obtained.

TLC: Rf 0.27 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (brs, 1H), 8.62 (brs, 1H), 7.75-7.64 (m, 3H),7.57 (s, 1H), 7.52-7.47 (m, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.31 (d, J=6.9Hz, 1H), 5.16 (d, J=4.5 Hz, 1H), 4.58-4.52 (m, 1H), 1.90 (t, J=7. 2 Hz,2H), 1.64-1.20 (m, 6H).

EXAMPLE 9(1) N-hydroxy-6-[2-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 9 using methyl6-(2-bromophenyl)-6-oxohexanoate instead of methyl6(3-bromophenyl)-6-oxohexanoate, the compound of the present inventionhaving the following physical data was obtained.

TLC: Rf 0.26 (ethyl acetate),

NMR (d₆-DMSO): δ 10.24 (s, 1H), 8.61 (s, 1H), 7.56 (d, J=7.5 Hz, 1H),7.49-7.46 (m, 2H), 7.40-7.24 (m, 4H), 7.11-7.09 (m, 1H), 5.03 (d, J=4.2Hz, 1H), 4.49-4.44 (m, 1H), 1.80 (t, J=7.5 Hz, 2H), 1.56-1.02 (m, 6H).

EXAMPLE 10N-hydroxy-6-[4-((1E)-2-phenylvinyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example10→example 2 using the compound prepared in reference example 6 andstyrene, the compound of the present invention having the followingphysical data was obtained.

TLC: Rf 0.34 (ethyl acetate),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 7.59-7.51 (m, 4H), 7.38-7.21 (m, 5H),7.21 (s, 1 2H), 4.49-4.45 (m, 1H), 1.89 (t, J=7.5 Hz, 2H), 1.601.12 (m,6H).

EXAMPLES 10(1) AND 10(2)

By the same procedure as a series of reactions of example 10 using acorresponding compound instead of styrene, the following compounds ofthe present invention were obtained.

EXAMPLE 10(1)N-hydroxy-6-[4-((1E)-2-(pyridinyl)vinyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.22 (ethyl acetate:methanol 9:1),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (s, 1H), 8.51 (d, J=5.4 Hz, 2H),7.58 (d, J=8.1 Hz, 2H), 7.53 (d, J=5.4 Hz, 2H), 7.51 (d, J=16.2 Hz, 1H),7.33 (d, J=8.1 Hz, 2H), 7.19 (d, J=16.2 Hz, 1H), 5.14 (d, J=4.8 Hz, 1H),4.52-4.46 (m, 1H), 1.89 (t, J=7.5 Hz, 2H), 1.60-1.10 (m, 6H).

EXAMPLE 10(2)N-hydroxy-6-[4-((1E)-2-(pyridin-2-yl)vinyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.22 (ethyl acetate:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 8.56-8.54 (m, 1H), 7.77(dt, J=7.5 Hz, 1.5 Hz, 1H), 7.64 (d, J=16.2 Hz, 1H), 7.59 (d, J=7.8 Hz,2H), 7.52 (d, J=8.1 Hz, 1H), 7.32 (d, J=7.8 Hz, 2H), 7.27 (d, J=16.2 Hz,1H), 7.25-7.21 (m, 1H), 5.13 (d, J=4.5 Hz, 1H), 4.52-4.80 (m, 1H), 1.90(t, J=7.5 Hz, 2H), 1.63-1.18 (m, 6H).

REFERENCE EXAMPLE 13 6-[4-(4-chlorophenyl)phenyl]-6-oxohexanoic acid

By the same procedure as a series of reactions of reference example 3using the compound prepared in reference example 1, the title compoundhaving the following physical data was obtained.

TLC: Rf 0.50 (ethyl acetate),

NMR (d₆-DMSO) δ 12.00 (s, 1H), 8.05 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4Hz, 2H), 7.79 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.4 Hz, 2H), 3.07 (t, J=6.6Hz, 2H), 2.27 (t, J=7.4 Hz, 2H), 1.80-1.50 (m, 4H).

REFERENCE EXAMPLE 14 6-[4-(4-chlorophenyl)phenyl]-6-hydroxy heptanoicacid

Under an atmosphere of argon, to a solution of the compound prepared inreference example 13 (560 mg) in tetrahydrofuran (20 mL) was added 0.82mmol/mL solution of methylmagnesium iodide in diethylether (10.8 mL) at0° C. The reaction mixture was stirred at room temperature for 1 hour.To the reaction mixture was added 1N hydrochloric acid and the mixturewas extracted with ethyl acetate. The extract was washed with water anda saturated aqueous solution of sodium chloride, dried over anhydrousmagnesium sulfate, and concentrated. The obtained residue was purifiedby column chromatography on silica gel (hexane:ethyl acetate=1:1) togive the title compound (442 mg) having the following physical data.

TLC: Rf 0.30 (hexane:ethyl acetate=1:2),

NMR (CDCl₃): δ 7.54-7.46 (m, 6H), 7.39 (d, J=8.4 Hz, 2H), 2.30 (t, J=7.2Hz, 2H), 1.84 (m, 2H), 1.66-1.56 (m, 2H), 1.58 (s, 3H), 1.45-1.32 (m,1H), 1.30-1.18 (m, 1H).

EXAMPLE 11 N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxyheptanamide

By the same procedure as a series of reactions of example 1→example 2using the compound prepared in reference example 14, the compound ofpresent invention having the following physical data was obtained.

TLC: Rf 0.27 (ethyl acetate),

NMR (d₆-DMSO): δ 10.24 (s, 1H), 8.60 (s, 1H), 7.67 (d, J=8.4 Hz, 2H),7.58 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H),4.87 (s, 1H), 1.85 (t, J=7.2 Hz, 2H), 1.74-1.60 (m, 2H), 1.44-1.34 (m,2H), 1.30-1.20 (m, 1H), 1.05-0.93 (m, 1H).

EXAMPLE 11(1)N-hydroxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxy-7-octenamide

By the same procedure as a series of reactions of reference example14→example 11 using vinylmagnesium bromide instead of methylmagnesiumiodide, the compound of present invention having the following physicaldata was obtained.

TLC: Rf 0.28 (ethyl acetate),

NMR (d₆-DMSO): δ 10.26 (s, 1H), 8.62 (s, 1H), 7.67 (d, J=8.5 Hz, 2H),7.59 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.5 Hz, 4H), 6.12 (dd, J=17.2, 10.6Hz, 1H), 5.21 (dd, J=17.2, 2.0 Hz, 1H), 5.15 (s, 1H), 5.00 (dd, J=10.6,2.0 Hz, 1H), 1.84 (m, 2H), 1.83-1.72 (m, 2H), 1.42 (m, 2H), 1.32-1.22(m, 1H), 1.12-1.00 (m, 1H).

EXAMPLE 11(2) N-hydroxy-6-(4-biphenyl)-6-hydroxyheptanamide

By the same procedure as a series of reactions of reference example14→example 11 using 6-(4-biphenyl)-4-oxohexanoic acid instead of thecompound prepared in reference example 13, the compound of presentinvention having the following physical data was obtained.

TLC: Rf 0.26 (ethyl acetate),

NMR (d₆-DMSO): δ 10.25 (s, 1H), 8.61 (s, 1H), 7.65-7.62 (m, 2H), 7.57(d, J=8.4 Hz, 2H), 7.46 (d, J=8.4 Hz, 2H), 7.43-7.41 (m, 2H), 7.35-7.29(m, 1H), 4.86 (s, 1H), 1.85 (t, J=7.2 Hz, 2H), 1.75-1.60 (m, 2H), 1.40(s, 3H), 1.42-1.18 (m, 3H), 1.04-0.91 (m. 1H).

REFERENCE EXAMPLE 15 6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanoic acid

By the same procedure as a series of reactions of reference example 14using 6-[4-(4-ethylphenyl)phenyl]-6-oxohexanoic acid instead of thecompound prepared in reference example 13, enantiomer mixture of thetitle compound was obtained. By the following method, (+) isomer and (−)isomer of the title compound, respectively, were obtained fromenantiomer mixture.

The enantiomer mixture (6.66 g), (1R,2R)-(+)-1,2-diphenylethylenediamine(4.33 g), ethyl acetate (80 mL) and hexane (20 mL) were mixed. Themixture was refluxed and dissolved completely. The mixture was cooled toroom temperature and the crystal precipitated. The precipitated crystalwas filtered and washed with a solution of hexane and ethyl acetate(hexane:ethyl acetate=1:1). The filtrate was concentrated. The obtainedresidue was used in the preparation of (−) isomer. The precipitatedcrystal was dissolved into ethyl acetate and washed with 1N hydrochloricacid, water and a saturated aqueous solution of sodium chloride anddried over anhydrous magnesium sulfate and concentrated to give (+)isomer of the title compound (2.44 g, 92.4% e.e, HPLC) having thefollowing physical data.

The residue concentrated the filtrate was dissolved into ethyl acetateand washed with 1N hydrochloric acid, water and a saturated aqueoussolution of sodium chloride, dried over anhydrous magnesium sulfate andconcentrated. The obtained residue,(1S,2S)-(−)-1,2-diphenylethylenediamine (2.32 g), ethyl acetate (50 mL)and hexane (10 mL) were mixed. The mixture was refluxed and dissolvedcompletely. The mixture was cooled to room temperature and crystalprecipitated. The precipitated crystal was filtered and washed with asolution of hexane and ethyl acetate (hexane:ethyl acetate=1:1). Theprecipitated crystal was dissolved into ethyl acetate and washed with 1Nhydrochloric acid, water and a saturated aqueous solution of sodiumchloride, dried over anhydrous magnesium sulfate and concentrated togive (−) isomer of the title compound (2.88 g, 89.9% e.e, HPLC) havingthe following physical data.

(+) Isomer:

TLC: Rf 0.46 (chloroform:methanol=9:1), Retention time: 6.99 min.Column: DAICEL CHIRAL CELAD-RH, 4.6×150 mm; Eluant:acetonitrile:water=65:35; UV: 256 nm; Flow rate: 1.0 mL/min.

(−) Isomer: TLC: Rf 0.46 (chloroform:methanol=9:1), Retention time:14.40 min. Column: DAICEL CHIRAL CELAD-RH, 4.6×150 mm; Eluant:acetonitrile:water=65:35; UV: 256nm; Flow rate: 1.0 mL/min.

EXAMPLE 12(+)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide

By the same procedure as a series of reactions of example 1→example 2using (+) isomer of the compound prepared in reference example 15, thecompound of the present invention having the following physical data wasobtained.

[α]_(D): +14.74 (c 0.555, methanol),

TLC: Rf 0.35 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.26 (s, 1H), 8.62 (s, 1H), 7.55 (d, J=8.4 Hz, 4H),7.45 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 4.85 (s, 1H), 2.62 (q,J=7.4 Hz, 2H), 1.86 (t, J=7.4 Hz, 2H), 1.78-1.56 (m, 2H), 1.55-1.21 (m,6H), 1.20 (t, J=7.4 Hz, 3H), 1.12-0.85 (m, 1H).

EXAMPLE 12(1)(−)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyheptanamide

By the same procedure as a series of reactions of example 12 using (−)isomer of the compound prepared in reference example 15, the compound ofthe present invention having the following physical data was obtained.

[α]_(D): −12.18 (c 0.74, methanol),

TLC: Rf 0.35 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.26 (s, 1H), 8.62 (s, 1H), 7.55 (d, J=8.4 Hz, 4H),7.45 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 4.85 (s, 1H), 2.62 (q,J=7.4 Hz, 2H), 1.86 (t, J=7.4 Hz, 2H), 1.78-1.56 (m, 2H), 1.55-1.21 (m,6H), 1.20 (t, J=7.4 Hz, 3H), 1.12-0.85 (m, 1H).

EXAMPLES 13(1)˜13(44)

By the same procedure as a series of reactions of reference example4→reference example 3→example 1→example 2 using a corresponding ketonederivative instead of the compound prepared in reference example 1, ifdesired, the conversion into the acid addition salts by conventionalmeans, the following compounds of the present invention were obtained.

EXAMPLE 13(1) (R)-(+)-N-hydroxy-6-(4-biphenyl)-6-hydroxyhexanamide

[α]_(D): +15.1 (c 0.245, methanol),

TLC: Rf 0.25 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.29 (s. 1H), 8.63 (s, 1H), 7.65-7.57 (m, 4H),7.46-7.30 (m, 5H), 5.13 (d, J=4.5 Hz, 1H), 4.54-4.49 (m, 1H), 1.91 (t,J=7.2 Hz, 2H), 1.64-1.44 (m, 4H), 1.40-1.22 (m, 2H).

EXAMPLE 13(2)(R)-(+)-N-hydroxy-6-[4-(4-methylphenyl)phenyl]-6-hydroxyhexanamide

[α]_(D): +11.53 (c 0.215, methanol),

TLC: Rf 0.22 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.62 (s, 1H), 7.56-7.51 (m, 4H), 7.34(d, J=8.1 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 5.11 (d, J=4.5 Hz, 1H),4.52-4.48 (m, 1H), 2.32 (s, 3H), 1.90 (t, J=7.5 Hz, 2H), 1.62-1.15 ( m,6H).

EXAMPLE 13(3)(R)-(+)-N-hydroxy-6-[4-(3-methylphenyl)phenyl]-6-hydroxyhexanamide

[α]_(D): +8.43 (c 0.37, methanol),

TLC: Rf 0.22 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.56 (d, J=8.1 Hz, 2H),7.44-7.29 (m, 5H), 7.14 (d, J=7.5 Hz, 1H), 5.12 (d, J=4.5 Hz, 1H),4.59-4.48 (m, 1H), 2.35 (s, 3H), 1.90 (t, J=7.2 Hz, 2H), 1.63-1.12 (m,6H).

EXAMPLE 13(4)(R)-(+)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

[α]_(D): +14.5 (c 0.195, methanol),

TLC: Rf 0.25 (chloroform:methanol:acetic acid 90:10:1),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.84 (d, J=8.4 Hz, 2H),7.65-7.58 (m, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.37 (s, 1H), 7.33-7.19 (m,2H), 5.19 (d, J=4.4 Hz, 1H), 4.59-4.45 (m, 1H), 1.89 (t, J=7.2 Hz, 2H),1.62-1.05 (m, 6H).

EXAMPLE 13(5)(R)-N-hydroxy-6-[4-(2-phenylethynyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.24 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.55-7.32 (m, 9H), 5.20(d, J=4.4 Hz, 1H), 4.56-4.44 (m, 1H), 1.89 (t, J=7.0 Hz, 2H), 1.60-1.08(m, 6H).

EXAMPLE 13(6)(R)-(+)-N-hydroxy-6-[4-(benzothiophen-2-yl)phenyl]-6-hydroxyhexanamide

[α]_(D): +13.88 (c 0.085, methanol),

TLC: Rf 0.25 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.96-7.92 (m, 1H),7.84-7.79 (m, 2H), 7.70 (d, J=9.0 Hz, 2H), 7.39 (d, J=9.0 Hz, 2H),7.36-7.28 (m, 2H), 5.18 (d, J=4.4 Hz, 1H), 4.59-4.48 (m, 1H), 1.89 (t,J=6.8 Hz, 2H), 1.65-1.10 (m, 6H).

EXAMPLE 13(7)(R)-N-hydroxy-6-[4-(4-(cyanomethyl)phenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.28 (ethyl acetate:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.67 (d, J=8.1 Hz, 2H),7.60 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H),5 14 (d, J=4.5 Hz, 1H), 4.52 (m, 1H), 4.06 (s, 2H), 1.91 (t, J=7.2 Hz,2H), 1.64-1.54 (m, 2H), 1.54-1.44 (m, 2H), 1.39-1.16 (m, 2H).

EXAMPLE 13(8)(R)-N-hydroxy-6-[4-(4-ethylphenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.29 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.42-10.20 (br, 1H), 8.75-8.55 (br, 1H), 7.56 (d,J=8.0 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.27 (d,J=8.0 Hz, 2H), 5.12 (d, J=4.4 Hz, 1H), 4.58-4.45 (m, 1H), 2.62 (q, J=7.6Hz, 2H), 1.91 (t, J=7.4 Hz, 2H), 1.70-1.10 (m, 6H), 1.19 (t, J=7.6 Hz,3H).

EXAMPLE 13(9)(R)-N-hydroxy-6-[4-(4-propylphenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.29 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.57 (d, J=8.4 Hz, 2H),7.54 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.4 Hz, 2H),5.12 (d, J=4.4 Hz, 1H), 4.58-4.44 (m, 1H), 2.57 (t, J=7.4 Hz, 2H), 1.92(t, J=7.4 Hz, 2H), 1.72-1.10 (m, 8H), 0.90 (t, J=7.8 Hz, 3H).

EXAMPLE 13(10)(R)-N-hydroxy-6-[4-(4-biphenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.26 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.78-7.60 (m, 8H),7.54-7.30 (m, 5H), 5.15 (d, J=4.4 Hz, 1H), 4.59-4.46 (m, 1H), 1.91 (t,J=6.8 Hz, 2H), 1.65-1.10 (m, 6H).

EXAMPLE 13(11)(R)-N-hydroxy-6-[4-(1-methylpiperidin-4-yl)phenyl]-6-hydroxyhexanamidehydrochloride

TLC: Rf 0.12 (methanol),

NMR (d₆-DMSO): δ 10.53 (br, 1H), 10.31 (s, 1H), 8.64 (br, 1H), 7.25 (d,J=8.2 Hz, 2H), 7.15 (d, J=8.2 Hz, 2H), 5.06 (br, 1H), 4.44 (t, J=6.0 Hz,1H), 3.46-3.28 (m, 3H), 3.09-2.96 (m, 2H), 2.73 (d-like, J=4.2 Hz, 3H),2.00-1.87 (m, 6H), 1.58-1.41 (m, 4H), 1.37-1.15 (m, 2H).

EXAMPLE 13(12)(R)-N-hydroxy-6-[4-(indol-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.33 (chloroform:methanol:acetic acid=60:10:1),

NMR (d₆-DMSO): δ 11.42 (s, 1H), 10.25 (s, 1H), 8.62 (s, 1H), 7.76 (d,J=8.1 Hz, 2H), 7.47 (d, J=7.5 Hz, 1H) 7.40-7.30 (m, 3H), 7.10-7.00 (m,1H), 7.00-6.90 (m, 1H), 6.81 (d, J=1.2 Hz, 1H), 5.12 (d, J=4.5 Hz, 1H),4.55-4.42 (m, 1H), 1.88 (t, J=7.4 Hz, 2H), 1.70-1.40 (m, 4H), 1.40-1.10(m, 2H).

EXAMPLE 13(13)(R)-(+)-N-hydroxy-6-[4-(4-cyanophenyl)phenyl]-6-hydroxyhexanamide

[α]_(D): +4.60 (c 0.265, methanol),

TLC: Rf 0.34 (ethyl acetate:methanol=19:1),

NMR (d₆-DMSO): δ 10.28 (brs, 1H), 8.63 (s, 1H), 7.90 (d, J=9.0 Hz, 2H),7.85 (d, J=9.0 Hz, 2H), 7.68 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H),5.19 (d, J=4.8 Hz, 1H), 4.58-4.51 (m, 1H), 1.90 (t, J=7.2 Hz, 2H),1.59-1.14 (m, 6H).

EXAMPLE 13(14)(R)-(+)-N-hydroxy-6-[4-phenyl-2-methylphenyl]-6-hydroxyhexanamide

[α]_(D): +18.31 (c 0.225, methanol),

TLC: Rf 0.37 (ethyl acetate:methanol=19:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.63-7.60 (m, 2H),7.46-7.39 (m, 5H), 7.34-7.28 (m, 1H), 5.02 (d, J=4.5 Hz, 1H), 4.72-4.68(m, 1H), 2.32 (s, 3H), 1.92 (t, J=6.9 Hz, 2H), 1.60-1.22 (m, 6H).

EXAMPLE 13(15) (R)-N-hydroxy-6-(4-cycloheptylphenyl)-6-hydroxyhexanamide

TLC: Rf 0.43 (ethyl acetate:methanol=9:1),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.63 (s, 1H), 7.17 (d, J=8.3 Hz, 2H),7.10 (d, J=8.3 Hz, 2H), 4.98 (d, J=4.5 Hz, 1H), 4.41 (m, 1H), 2.61 (m,1H), 1.89 (t, J=7.2 Hz, 2H), 1.81-1.41 (m, 16H), 1.37-1.10 (m, 2H).

EXAMPLE 13(16)(R)-N-hydroxy-6-(9,10-dihydrophenanthren-2-yl)-6-hydroxyhexanamide

TLC: Rf 0.37 (ethyl acetate:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.63 (s, 1H), 7.77 (d, J=7.2 Hz, 1H),7.73 (d, J=8.1 Hz, 1H), 7.31-7.17 (m, 5H), 5.10 (d, J=4.5 Hz, 1H), 4.47(m, 1H), 2.79 (s, 4H), 1.91 (t, J=7.2 Hz, 2H), 1.63-1.44 (m, 4H),1.41-1.17 (m, 2H).

EXAMPLE 13(17)(R)-N-hydroxy-6-[4-(1-ethoxycarbonylpiperidin-4-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.42 (ethyl acetate:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.21 (d, J=8.3 Hz, 2H),7.15 (d, J=8.3 Hz, 2H), 5.01 (d, J=4.2 Hz, 1H), 4.42 (m, 1H), 4.11-4.01(m, 2H), 4.01 (q, J=7.0 Hz, 2H), 2.83 (m, 2H), 2.65 (m, 1H), 1.89 (t,J=7.2 Hz, 2H), 1.75-1.71 (m, 2H), 1.55-1.42 (m, 6H), 1.37-1.25 (m, 2H),1.18 (t, J=7.0 Hz, 3H).

EXAMPLE 13(18)(R)-(+)-N-hydroxy-[4-(4-(N-methylcarbamoyl)phenyl)phenyl]-6-hydroxyhexanamide

[α]_(D): +12.37 (c 0.08, methanol),

TLC: Rf 0.33 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (brs, 1H), 8.48-8.43 (m, 1H), 7.89(d, J=8.4 Hz, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.65 (d, J=85.4 Hz, 2H), 7.39(d, J=8.4 Hz, 2H), 5.18 (brs, 1H), 4.56-4.50 (m, 1H), 2.78 (d , J=4.8Hz, 3H), 1.90 (t, J=7.5 Hz, 2H), 1.63-1.11 (m, 6H).

EXAMPLE 13(19)(R)-(+)-N-hydroxy-6-(4-cyclohexylphenyl)-6-hydroxyhexanamide

[α]_(D): +12.65 (c 0.16, methanol),

TLC: Rf 0.31 (chloroform:methanol=19:1),

NMR (d₆-DMSO): δ 10.27 (s, 1H), 8.62 (s, 1H), 7.18 (d, J=8.1 Hz, 2H),7.12 (d, J=8.1 Hz, 2H), 4.98 (d, J=4.2 Hz, 1H), 4.42-4.36 (m, 1H),2.45-2.39 (m, 1H), 1.89 (t, J=7.2 Hz, 2H), 1.80-1.09 (m, 17H).

EXAMPLE 13(20)(R)-N-hydroxy-6-[4-(5-hydroxybenzofuran-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.27 (chloroform:methanol:acetic acid=60:10:1),

NMR (d₆-DMSO): δ 10.25 (s, 1H), 9.18 (s, 1H), 8.60 (s, 1H), 7.77 (d,J=8.2 Hz, 2H), 7.38 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.8 Hz, 1H), 7.19 (s,1H), 6.89 (d, J=2.6 Hz, 1H), 6.69 (dd, J=8.8, 2.6 Hz, 1H), 5.17 (d,J=4.4 Hz, 1H), 4.60-4.40 (m, 1H), 1.88 (t, J=7.1 Hz, 2H), 1.70-1.10 (m,6H).

EXAMPLE 13(21)(R)-N-hydroxy-6-[4-(2-(4-methylphenyl)ethynyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.41 (chloroform:methanol:acetic acid=60:10:1),

NMR (d₆-DMSO): δ 10.27 (s, 1H), 8.65 (s, 1H), 7.50-7.35 (m, 4H), 7.31(d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 5.18 (d, J=4.4 Hz, 1H),4.60-4.40 (m, 1H), 2.30 (s, 3H), 1.87 (t, J=7.1 Hz, 2H), 1.65-1.00 (m,6H).

EXAMPLE 13(22)(R)-N-hydroxy-6-[4-((1E)-2-(4-methylphenyl)vinyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.43 (chloroform:methanol:acetic acid 60:10:1),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 7.53-7.38 (m, 4H), 7.26 (d, J=8.0 Hz,2H), 7.20-7.05 (m, 4H), 4.45 (t, J=6.4 Hz, 1H), 2.25 (s, 3H), 1.87 (t,J=7.0 Hz, 2H), 1.70-1.00 (m, 6H).

EXAMPLE 13(23)(R)-N-hydroxy-6-[4-(4-trifuoromethoxyphenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.25 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.76 (d, J=8.7 Hz, 2H),7.61 (d, J=8.7 Hz, 2H), 7.43-7.38 (m, 4H), 5.15 (d, J=4.5 Hz, 1H),4.55-4.95 (m, 1H), 1.90 (t, J=7.5 Hz, 2H), 1.63-1.12 (m, 6H).

EXAMPLE 13(24)(R)-N-hydroxy-6-[4-(4-ethylthiophenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.40 (ethyl acetate:methanol=4:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.59 (d, J=8.4 Hz, 2H),7.58 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 4H), 5.13 (br, 1H), 4.51 (t,J=6.0 Hz, 1H), 3.00 (q, J=7.2 Hz, 2H), 1.91 (t, J=7.0 Hz, 2H), 1.58 (m,2H), 1.48 (m, 2H), 1.39-1.16 (m, 2H), 1.24 (t, J=7.2 Hz, 3H).

EXAMPLE 13(25)(R)-N-hydroxy-6-[4-(4-methoxyphenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.23 (ethyl acetate:methanol=4:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.64 (s, 1H), 7.57 (d, J=8.5 Hz, 2H),7.53 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 6.99 (d, J=8.5 Hz, 2H),5.11 (d, J=4.2 Hz, 1H), 4.50 (m, 1H), 3.77 (s, 3H), 1.91 (t, J=7.2 Hz,2H), 1.57 (m, 2H), 1.48 (m, 2H), 1.39-1.16 (m, 2H).

EXAMPLE 13(26)(R)-N-hydroxy-6-[4-(4-(1-methylethyl)phenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.20 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (brs, 1H), 7.55 (d, J=8.4 Hz, 2H),7.54 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H),5.11 (brs, 1H), 4.50 (t, J=6.0 Hz, 1H), 2.98-2.82 (m, 1H), 1.90 (t,J=7.2 Hz, 2H), 1.62-1.20 (m, 6H), 1.21 (d, J=6.9 Hz, 6H).

EXAMPLE 13(27)(R)-N-hydroxy-6-[4-(4-(N,N-dimethylcarbamoylmethyl)phenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.21 (chloroform:methanol 9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.57 (d, J=8.0 Hz, 4H),7.37 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 5.13 (d, J=4.4 Hz, 1H),4.59-4.46 (m, 1H), 3.71 (s, 2H), 3.01 (s, 3H), 2.83 (s, 3H), 1.91 (t,J=7.0 Hz, 2H), 1.65-1.10 (m, 6H).

EXAMPLE 13(28)(R)-N-hydroxy-6-[4-benzothiazol-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.24 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 8.18-8.12 (m, 1H),8.09-7.98 (m, 3H), 7.60-7.40 (m, 4H), 5.38-5.22 (m, 1H), 4.65-4.55 (m,1H), 1.92 (t, J=7.4 Hz, 2H), 1.70-1.15 (m, 6H).

EXAMPLE 13(29)(R)-N-hydroxy-6-[4-(4-(methoxymethoxymethyl)phenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.30 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.63 (d, J=8.0 Hz, 2H),7.59 (d, J=8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 Hz, 2H),5.14 (d, J=4.4 Hz, 1H, 4.66 (s, 2H), 4.60-4.45 (m, 3H), 3.31 (s, 3H),1.92 (t, J=7.0 Hz, 2H), 1.70-1.12 (m, 6H).

EXAMPLE 13(30)(R)-(+N-hydroxy-6-[4-(6-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

[α]_(D): +7.31 (c 0.19, methanol),

TLC: Rf 0.15 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (brs, 1H), 8.07 (d, J=8.7 Hz, 2H),7.66 (d, J=8.7 Hz, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.40 (d, J=2.4 Hz, 1H),6.99 (dd, J=8.7 Hz, 2.4 Hz, 1H), 5.29 (brs, 1H), 4.60-4.56 (m, 1H), 3.83(s, 3H), 1.90 (t, J=7.5 Hz, 2H), 1.63-1.20 (m, 6H).

EXAMPLE 13(31)(R)-N-hydroxy-6-[4-(6-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.28 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.90-8.30 (br, 1H), 8.11 (d, J=8.4 Hz,2H), 7.65 (d, J=8.2 Hz, 1H), 7.59 (d, J=1.0 Hz, 1H), 7.53 (d, J=8.4 Hz,2H), 7.21 (dd, J=8.2,1.0 Hz, 1H), 5.60-4.90 (br, 1H), 4.60 (t, J=6.2 Hz,1H), 2.46 (s, 3H), 1.91 (t, J=7.4 Hz, 2H), 1.68-1.12 (m, 6H).

EXAMPLE 13(32)(R)-N-hydroxy-6-[4-(4-methoxymethylphenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.39 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 9.10-8.10 (br, 1H), 7.62 (d, J=8.4 Hz,2H), 7.59 (d, J=8.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 4H), 5.50-4.70 (br, 1H),4.52 (t, J=6.2 Hz, 1H), 4.43 (s, 2H), 3.30 (s, 3H), 1.91 (t, J=7.4 Hz,2H), 1.70-1.10 (m, 6H).

EXAMPLE 13(33)(R)-N-hydroxy-6-[4-(5-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.13 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.25 (s, 1H), 8.62 (s, 1H), 8.08 (d, J=8.3 Hz, 2H),7.63 (d, J=9.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.31 (d, J=2.4 Hz, 1H),6.96 (dd, J=9.0, 2.4 Hz, 1H), 5.29 (d, J=4.5 Hz, 1H), 4.62-4.52 (m, 1H),3.79 (s, 3H), 1.88 (t, J=7.2 Hz, 2H), 1.65-1.10 (m, 6H).

EXAMPLE 13(34)(R)-N-hydroxy-6-[4-(4-methoxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.28 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.32 (s, 1H), 8.64 (s, 1H), 8.12 (d, J=8.4 Hz, 2H),7.53 (d, J=8.4 Hz, 2H), 7.40-7.28 (m, 2H), 7.02-6.90 (m, 1H), 5.31 (d,J=4.4 Hz, 1H), 4.66-4.54 (m, 1H), 3.99 (s, 3H), 1.92 (t, J=7.4 Hz, 2H),1.70-1.10 (m, 6H).

EXAMPLE 13(35)(R)-(+)-N-hydroxy-6-[4-(4-(piperidin-1-ylmethyl)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

[α]_(D): +6.17 (c 0.1 2, methanol),

TLC: Rf 0.21 (chloroform:methanol=4:1),

NMR (d₆-DMSO): δ 10.41-10.31 (m, 2H), 7.73 (d, J=8.1 Hz, 2H), 7.65-7.61(m, 4H), 7.39 (d, J=8.1 Hz, 2H), 4.52 (t, J=6.3 Hz, 1H), 4.26 (d, J=5.1Hz, 2H), 3.32-3.27 (m, 2H), 2.91-2.78 (m, 2H), 1.90 (t, J=7.2 Hz, 2H).

EXAMPLE 13(36)(R)-(+)-N-hydroxy-6-[4-(4-hydroxybenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

[α]_(D): +6.33 (c 0.12, methanol),

TLC: Rf 0.42 (chloroform:methanol=17:3),

NMR (d₆-DMSO): δ 10.35 (s, 1H), 10.30 (s, 1H), 8.63 (s, 1H), 8.10 (d,J=8.1 Hz, 2H), 7.52 (d, J=8.1 Hz, 2H), 7.21-7.14 (m, 2H), 6.78-6.75 (m,1H), 5.30 (d, J=4.5 Hz, 1H), 4.62-4.54 (m, 1H), 1.91 (t, J=7.2 H z, 2H),1.62-1.16 (m, 6H).

EXAMPLE 13(37)(R)-N-hydroxy-6-[4-(6-hydroxybenzoxazol-2-yl)phenyl]-6-hydroxylhexanamide

TLC: Rf 0.21 (chloroform:methanol:acetic acid=60:10:1),

NMR (d₆-DMSO): δ 10.25 (s, 1H), 9.80 (s, 1H), 8.60 (s, 1H), 8.03 (d,J=8.2 Hz, 2H), 7.56-7.42 (m, 3H), 7.05 (d, J=2.2 Hz, 1H), 6.81 (dd,J=8.4, 2.2 Hz, 1H), 5.25 (d, J=4.4 Hz, 1H), 4.62-4.50 (m, 1H), 1.88 (t,J=7.4 Hz, 2H), 1.70-1.10 (m, 6H).

EXAMPLE 13(38)(R)-N-hydroxy-6-[4-((1E)-2-(4-methylthiophenyl)vinyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.22 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.25 (s, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.49 (d, J=9.0Hz, 2H), 7.30-7.05 (m, 6H), 4.45 (t, J=6.1 Hz, 1H), 2.45 (s, 3H), 1.87(t, J=7.2 Hz, 2H), 1.65-1.00 (m, 6H).

EXAMPLE 13(39)(R)-N-hydroxy-6-[4-(5-methoxybenzofuran-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.27 (chloroform:methanol 9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 7.83 (d, J=8.4 Hz, 2H),7.50 (d, 8.8 Hz, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.30 (s, 1H), 7.14 (d,J=2.6 Hz, 1H), 6.88 (dd, J=8.8, 2.6 Hz, 1H), 5.21 (d, J=4.4 Hz, 1H),4.60-4.48 (m, 1H), 3.79 (s, 3H), 1.91 (t, J=7.0 Hz, 2H), 1.68-1.14 (m,6H).

EXAMPLE 13(40)(R)-N-hydroxy-6-[4-(5-methylthiobenzofuran-2-yl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.27 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.82-8.42 (br, 1H), 7.84 (d, J=8.4 Hz,2H), 7.60-7.52 (m, 2H), 7.43 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.23 (dd,J=8.8, 2.0 Hz, 1H), 5.42-4.96 (br, 1H), 4.54 (t, J=6.4 Hz, 1H), 2.51 (s,3H), 1.92 (t, J=7.0 Hz, 2H), 1.70-1.12 (m, 6H).

EXAMPLE 13(41)(R)-(+)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethyl)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

[α]_(D): +22.11 (c 0.635, dimethylformamide),

TLC: Rf 0.12 (chloroform:methanol=7:3),

NMR (d₆-DMSO): δ 10.60 (s, 1H), 10.32 (s, 1H), 8.62 (s, 1H), 7.62 (d,J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.38-7.33 (m, 4H), 5.14 (d, J=4.2Hz, 1H), 4.54-4.48 (m, 1H), 3.30-3.25 (m, 2H), 3.06-3.00 (m, 2H), 2.78(s, 6H), 1.91 (t, J=7.2 Hz, 2H), 1.62-1.15 (m, 6H).

EXAMPLE 13(42)(R)-(+)-N-hydroxy-6-[4-(4-(2-(dimethylamino)ethoxy)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

[α]_(D): +20.47 (c 1.005, dimethylformamide),

TLC: Rf 0.32 (chloroform:methanol=4:1),

NMR (d₆-DMSO): δ 10.56 (br, 1H), 10.32 (s, 1H), 8.63 (s, 1H), 7.61 (d,J=8.5 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.07 (d,J=8.5 Hz, 2H), 5.12 (d, J=4.2 Hz, 1H), 4.05 (m, 1H), 4.39 (t, J=5.0 Hz,2H), 3.50 (t, J=5.0 Hz, 2H), 2.83 (s, 6H), 1.91 (t, J=7.2 Hz, 2H), 1.57(m, 2H), 1.50 (m, 2H), 1.39-1.17 (m, 2H).

EXAMPLE 13(43)(R)-(+)-N-hydroxy-6-[4-(4-(2-(diethylamino)ethyl)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

[α]_(D): +18.58 (c 0.93, dimethylformamide),

TLC: Rf 0.25 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.47 (brs, 1H), 10.32 (s, 1H), 8.62 (brs, 1H), 7.61(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.37(d, J=8.4 Hz, 2H), 5.13 (brs, 1H), 4.53-4.49 (m, 1H), 3.31-3.01 (m, 8H),1.90 (t, J=6.9 Hz, 2H), 1.62-1.15 (m, 6H), 1.23 (t, J=6.9 Hz, 6H).

EXAMPLE 13(44)(R)-N-hydroxy-6-[4-(4-(2-hydroxyethyl)phenyl)phenyl]-6-hydroxyhexanamide

TLC: Rf 0.28 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.56 (d, J=8.1 Hz, 2H),7.53 (d, J=8.1 Hz, 2H), 7.36 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H),5.12 (d, J=4.5 Hz, 1H), 4.64 (t, J=5.3 Hz, 1H), 4.51 (m, 1H), 3.61 (m,2H), 2.74 (t, J=7.0 Hz, 2H), 1.91 (t, J=7.0 Hz, 2H), 1.63-1.43 (m, 4H),1.40-1.15 (m, 2H).

EXAMPLES 14(1)-14(5)

By the same procedure as a series of reactions of reference example5→reference example 3→example 1→example 2 using a corresponding ketonederivative instead of the compound prepared in reference example 1, ifdesired, the conversion into the acid addition salts by conventionalmeans., the following compounds of the present invention were obtained.

EXAMPLE 14(1)(S)-(−)-N-hydroxy-6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanamide

[α]_(D): −26.3 (c 0.99, dimethylformamide),

TLC: Rf 0.21 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.60 (d, J=8.4 Hz, 2H),7.58 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz, 2H),5.12 (d, J=3.9 Hz, 1H), 4.51 (m, 1H), 2.50 (s, 3H), 1.91 (t, J=7.5 Hz,2H), 1.65-1.15 (m, 6H).

EXAMPLE 14(2)(S)-(−)-N-hydroxy-6-[4-(2-(4-methylthiophenyl)ethynyl)phenyl]-6-hydroxyhexanamide

[α]_(D): −33.4 (c 0.99, dimethylformamide),

TLC: Rf 0.19 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.28 (s, 1H), 8.62 (s, 1H), 7.47 (d, J=8.4 Hz, 2H),7.45 (d, J=8.4 Hz, 2H), 7.33 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H),5.20 (d, J=4.8 Hz, 1H), 4.51 (m, 1H), 2.49 (s, 3H), 1.90 (t, J=7.2 Hz,2H), 1.60-1.40 (m, 4H), 1.35-1.15 (m, 2H).

EXAMPLE 14(3)(S)-(−)-N-hydroxy-6-[4-(benzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

[α]_(D): −11.5 (c 0.81, methanol),

TLC: Rf 0.21 (chloroform:methanol 9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 8.15 (d, J=8.4 Hz, 2H),7.82-7.75 (m, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.45-7.30 (m, 2H), 5.32 (d,J=4.8 Hz, 1H), 4.65-4.56 (m, 1H), 1.92 (t, J=7.0 Hz, 2H), 1.70-1.20 (m,6H).

EXAMPLE 14(4)(S)-(−)-N-hydroxy-6-[4-(5-methylbenzoxazol-2-yl)phenyl]-6-hydroxyhexanamide

[α]_(D): −33.4 (c 0.99, dimethylformamide),

TLC: Rf 0.23 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (d, J=1.5 Hz, 1H), 8.63 (d, J=1.5 Hz, 1H), 8.12(d, J=8.1 Hz, 2H), 7.64 (d, J=8.4 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.53(d, J=8.1 Hz, 2H), 7.23 (dd, J=8.4, 1.2 Hz, 1H), 5.32 (d, J=4.2, 1H),4.60 (m, 1H), 2.43 (s, 3H), 1.91 (t, J=6.9 Hz, 2H), 1.70-1.20 (m, 6H).

EXAMPLE 14(5)(S)-(−)-N-hydroxy-6-[4-(4-(dimethylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

[α]_(D): −5.39 (c 0.495, water),

TLC: Rf 0.25 (chloroform:methanol=2:1).

NMR (d₆-DMSO): δ 10.31 (m, 2H), 8.64 (s, 1H), 7.76 (d, J=8.0 Hz, 2H),7.65 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz, 2H),5.16 (m, 1H), 4.53 (m, 1H), 4.29 (s, 2H), 2.71 (s, 6H), 1.91 (t, J=7.0Hz, 2H), 1.65-1.15 (m, 6H).

EXAMPLE 15(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example4→reference example 3→example 1 using methyl6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-oxohexanoate instead ofthe compound prepared in reference example 1, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.46 (chloroform:methanol=6:1),

NMR (CDCl₃): δ 7.74 (brs, 1H), 7.54 (d, J=8.1 Hz, 2H), 7.53 (d, J=8.1Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.38 (d, J=8.1 Hz, 2H), 4.74-4.70 (m,1H), 3.73-3.70 (m, 4H), 3.30 (s, 3H), 2.48-2.45 (m, 4H), 2.19-2.08 (m,2H), 1.91-1.34 (m, 6H), 1.41 (s, 6H).

EXAMPLE 15(1)(R)-N-(1-methoxy-1-methyl)ethoxy-4-[4-(4-(dipropylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 15 usingmethyl 6-[4-(4-dipropylaminomethyl)phenyl)phenyl]-6-oxohexanoate insteadof methyl 6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-oxohexanoate,the compound of the present invention having the following physical datawas obtained.

TLC: Rf 0.31 (chloroform:methanol=9:1),

NMR (CDCl₃): δ 7.76 (br, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.52 (d, J=8.4 Hz,2H), 7.39 (d, J=8.4 Hz, 4H), 4.72 (dd, J=7.0, 5.8 Hz, 1H), 3.59 (s, 2H),3.30 (s, 3H), 2.40 (t-like, J=7.5 Hz, 4H), 2.34 (m, 2H), 1.84-1.67 (m,4H), 1.56-1.36 (m, 2H), 1.50 (m, J=7.5 Hz, 4H), 1.41 (s, 6H), 0.87 (t,J=7.5 Hz, 6H).

EXAMPLE 16(R)-(+)-N-hydroxy-6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

By the same procedure as a series of reactions of example 2 using thecompound prepared in example 15 instead of the compound prepared inexample 1 and the conversion into the acid addition salts byconventional means., the compound of the present invention having thefollowing physical data was obtained.

[α]_(D): +6.17 (c 0.12, methanol),

TLC: Rf 0.21 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 11.30 (brs, 1H), 10.32 (brs, 1H), 7.73 (d, J=8.7 Hz,2H), 7.67 (d, J=8.7 Hz, 2H), 7.63 (d, J=8.7 Hz, 2H), 7.39 (d, J=8.7 Hz,2H), 4.52 (t, J=6.3 Hz, 1H), 4.34 (d, J=5.1 Hz, 2H), 3.94-3.75 (m, 4H),3.20-2.95 (m, 4H), 1.93 (t, J=7.2 Hz, 2H), 1.65-1.15 (m, 6H).

EXAMPLE 16(1)(R)-(+)-N-hydroxy-6-[4-(4-(dipropylaminomethyl)phenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 16 using thecompound prepared in example 15(1), or the conversion into the acidaddition salts by conventional means, the compounds of the presentinvention having the following physical data were obtained.

Free Form:

[α]_(D): +20.85 (c 1.01, dimethylformamide),

TLC: Rf 0.37 (chloroform:methanol=6:1),

NMR (d₆-DMSO): δ 10.26 (br, 1H), 8.65 (br, 1H), 7.58 (d, J=8.4 Hz, 4H),7.36 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 5.12 (br, 1H), 4.51 (t,J=6.0 Hz, 1H), 3.52 (s, 2H), 2.33 (t, J=7.2 Hz, 4H), 1.91 (t, J=7.2 Hz,2H), 1.64-1.55 (m, 2H), 1.51-1.37 (m, 6H), 1.36-1.17 (m, 2H), 0.82 (t,J=7.2 Hz, 6H).

Hydrochloride:

TLC: Rf 0.37 (chloroform:methanol=6:1),

NMR (d₆-DMSO): δ 10.58 (br, 1H), 10.32 (s, 1H), 8.62 (br, 1H), 7.74 (d,J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.40 (d,J=8.4 Hz, 2H), 5.17 (br, 1H), 4.53 (t, J=6.3 Hz, 1H), 4.32 (s, 2H), 2.93(m, 4H), 1.91 (t, J=7.2 Hz, 2H), 1.82-1.66 (m, 4H), 1.65-1.55 (m, 2H),1.48 (m, 2H), 1.40-1.20 (m, 2H), 0.86 (t, J=7.2 Hz, 6H).

EXAMPLES 17(1) AND 17(2)

By the same procedure as a series of reactions of reference example4→reference example 3→example 1→example 2 using methyl6-(5-phenylthiophen-2-yl)-6-oxohexanoate or methyl6-(5-phenylbenzofuran-2-yl)-6-oxohexanoate instead of the compoundprepared in reference example 1, the following compounds of the presentinvention were obtained.

EXAMPLE 17(1)(R)-N-hydroxy-6-(5-phenylthiophen-2-yl)-6-hydroxyhexanamide

TLC: Rf 0.19 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.42-10.20 (br, 1H), 8.80-8.55 (br, 1H), 7.64-7.56 (m,2H), 7.43-7.20 (m, 4H), 6.90 (d, J=3.2 Hz, 1H), 5.59 (d, J=4.0 Hz, 1H),4.80-4.65 (m, 1H), 1.93 (t, J=7.4 Hz, 2H), 1.76-1.15 (m, 6H).

EXAMPLE 17(2)(R)-N-hydroxy-6-(5-phenylbenzofuran-2-yl)-6-hydroxyhexanamide

TLC: Rf 0.28 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.65 (s, 1H), 7.83 (m, 1H), 7.70-7.52(m, 4H), 7.50-7.28 (m, 3H), 6.75 (s, 1H), 5.53 (d, J=5.4 Hz, 1H),4.72-4.58 (m, 1H), 1.93 (t, J=7.4 Hz, 2H), 1.84-1.62 (m, 2H), 1.60-1.18(m, 4H).

REFERENCE EXAMPLE 16 (R)-benzyl6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydroxyhexanoate

By the same procedure as a series of reactions of reference example 4using benzyl 6-[4-(4-methoxycarbonyl)phenyl)phenyl]-6-oxohexanoateinstead of the compound prepared in reference example 1, the titlecompound having the following physical data was obtained.

TLC: Rf 0.19 (chloroform:ethyl acetate=19:1).

REFERENCE EXAMPLE 17(R)-6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydroxyhexanoic acid

To a solution of the compound prepared in reference example 16 (1.36 g)in methanol (20 mL) and tetrahydrofuran (10 mL) was added 10% palladiumcarbon (136 mg). Under atmosphere of hydrogen, the reaction mixture wasstirred at room temperature for 1.5 hours. The reaction mixture wasfiltered and concentrated. The obtained residue was washed with etherand dried to give the title compound (951 mg) having the followingphysical data.

TLC: Rf 0.32 (chloroform:methanol=9:1).

EXAMPLE 18(R)-N-hydroxy-6-[4-(4-(methoxycarbonyl)phenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 1→example 2using the compound prepared in reference example 17, the compound ofpresent invention having the following physical data was obtained.

TLC: Rf 0.28 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.64 (s, 1H), 8.02 (d, J=8.4 Hz, 2H),7.81 (d, J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H),5.18 (d, J=4.4 Hz, 2H), 4.61-4.48 (m, 1H), 3.86 (s, 3H), 1.91 (t, J=7.4Hz, 2H), 1.67-1.10 (m, 6H).

EXAMPLE 19(R)-N-hydroxy-6-[4-(4-carboxyphenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 1→referenceexample 3→example 2 using the compound prepared in reference example 17,the compound of present invention having the following physical data wasobtained.

TLC: Rf 0.16 (chloroform:methanol:acetic acid=90:10:1),

NMR (d₆-DMSO): δ 10.31 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4Hz, 2H), 7.66 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 5.40-4.90 (br.1H), 4.61-4.47 (m, 1H), 1.92 (t, J=7.0 Hz, 2H), 1.70-1.10 (m, 6H).

REFERENCE EXAMPLE 18 (R)-methyl6-[4-(4-methylthiophenyl)phenyl]-6-hydroxyhexanoate

By the same procedure as a series of reactions of reference example 4using methyl 6-[4-(4-methylthiophenyl)phenyl]-6-oxohexanoate instead ofthe compound prepared in reference example 1, the title compound havingthe following physical data was obtained.

TLC: Rf 0.25 (hexane:ethyl acetate=2:1),

NMR (CDCl₃): δ 7.57-7.49 (m, 4H), 7.39 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4Hz, 2H), 4.72 (t, J=6.2 Hz, 1H), 3.65 (s, 3H), 2.32 (t, J=7.4 Hz, 2H),1.88-1.25 (m, 6H).

REFERENCE EXAMPLE 19 (R)-methyl6-[4-(4-methylsulfonylphenyl)phenyl]-6-hydroxyhexanoate

To a solution of the compound prepared in reference example 18 (335 mg)in dichloromethane (10 mL) was added m-chloroperbenzoic acid (504 mg) at0° C. The reaction mixture was stirred at 0° C. for 1 hour. To thereaction mixture was added an aqueous solution of sodium thiosulfate andthe mixture was extracted with ethyl acetate. The extract was washedwith water and a saturated aqueous solution of sodium chloride, driedover anhydrous sodium sulfate and concentrated to give the titlecompound (349 mg) having the following physical data.

TLC: Rf 0.51 (hexane:ethyl acetate=1:4),

NMR (CDCl₃): δ 8.00 (d, J=8.4 Hz, 2H), 7.76 (d, J=8.4 Hz, 2H), 7.59 (d,J=8.4 Hz, J=2H), 7.46 (d, J=8.4 Hz, 2H), 4.80-4.72 (m, 1H), 3.66 (s,3H), 3.09 (s, 3H), 2.32 (t, J=7.5 Hz, 2H), 1.90-1.30 (m, 6H).

EXAMPLE 20(R)-(+)-N-hydroxy-6-[4-(4-methylsulfonylphenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example3→example 1→example 2 using the compound prepared in reference example19 instead of the compound prepared in reference example 2, the compoundof the present invention having the following physical data wasobtained.

[α]_(D): +9.84 (c 0.125, methanol),

TLC: Rf 0.12 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.29 (s, 1H), 8.63 (s, 1H), 7.97 (d, J=8.7 Hz, 2H),7.91 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H),5.19 (d, J=4.5 Hz, 1H), 4.59-4.51 (m, 1H), 3.23 (s, 1H), 1.90 (t, J=7.5Hz, 2H), 1.62-1.18 (m, 6H).

REFERENCE EXAMPLE 20 (R)-methyl6-[4-(4-hydroxymethylphenyl)phenyl]-6-hydroxyhexanoate

By the same procedure as a series of reactions of reference example 4using methyl 6-[4-(4-formylphenyl)phenyl]-6-oxohexanoate instead of thecompound prepared in reference example 1, the title compound having thefollowing physical data was obtained.

TLC: Rf 0.27 (hexane:ethyl acetate=1:1),

NMR (CDCl₃): δ 7.59 (d, J=8.4 Hz, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.44 (d,J=8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 4.78-4.66 (m, 3H), 3.66 (s, 3H),2.32 (t, J=7.6 Hz, 2H), 2.02-1.20 (m, 6H).

EXAMPLE 21(R)-N-hydroxy-6-[4-(4-hydroxymethylphenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example3→example 1→example 2 using the compound prepared in reference example20 instead of the compound prepared in reference example 2, the compoundof the present invention having the following physical data wasobtained.

TLC: Rf 0.13 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.30 (s, 1H), 8.80-8.50 (br. 1H), 7.60 (d, J=8.0 Hz,2H), 7.58 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 4H), 5.40-5.00 (br, 2H),4.60-4.40 (m, 3H), 1.91 (t, J=7.0 Hz, 2H), 1.70-1.10 (m, 6H).

EXAMPLE 22 N-methoxy-6-[4-(4-chlorophenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of example 1 usingmethoxylamine instead of (1-methoxy-1-methylethyl)hydroxyamine, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.27 (ethyl acetate),

NMR (CDCl₃): δ 8.21 (br, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.49 (d, J=8.0 Hz,2H), 7.39 (d, J=8.0 Hz, 4H), 4.74-4.70 (m, 1H), 3.72 (s, 3H), 2.44-2.04(m, 3H), 1.90-1.62 (m, 4H), 1.58-1.34 (m, 2H).

EXAMPLE 23(R)-(+)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(5-methylbenzoxazol-2-yl)phenyl]pentan-1-ol

A solution of the compound prepared in example 6 (3 g) in toluene (100mL) was stirred at 100° C. for 3 hours. The reaction mixture wasconcentrated. The obtained residue was washed with isopropyl ether anddried to give the compound (2.83 g) of the present invention having thefollowing physical data.

[α]_(D): +24.59 (c 0.81, dimethylformamide),

TLC: Rf 0.21 (hexane:ethyl acetate=2:1),

NMR (CDCl₃): δ 8.21 (d, J=8.4 Hz, 2H), 7.54 (brs, 1H), 7.49 (d, J=8.4Hz, 2H), 7.45 (d, J=8.4 Hz, 1H), 7.17-7.14 (m, 1H), 4.79-4.75 (m, 1H),2.48 (s, 3H), 2.30 (t, J=7.2 Hz, 2H), 1.91-1.33 (m, 6H), 1.53 (s, 6H).

EXAMPLES 23(1) AND 23(2)

Using the compound prepared in example 6(3) or (4) instead of thecompound prepared in example 6, if desired, the conversion into the acidaddition salts by conventional means, the following compounds of thepresent invention were obtained.

EXAMPLE 23(1)(R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(4-methylthiophenyl)phenyl]pentan-1-ol

TLC: Rf 0.57 (hexane:ethyl acetate=1:1),

NMR (CDCl₃): δ 7.54 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.5 Hz, 2H), 7.39 (d,J=8.5 Hz, 2H), 7.32 (d, J=8.5 Hz, 2H), 4.71 (m, 1H), 2.52 (s, 3H), 2.30(t, J=7.5 Hz, 2H), 1.94-1.72 (m, 2H), 1.66 (m, 2H), 1.57-1.35 (m, 2H),1.53 (s, 3H), 1.52 (s, 3H).

EXAMPLE 23(2)(R)-5-(5,5-dimethyl-1,4,2-dioxazolin-3-yl)-1-[4-(4-(dimethylaminomethyl)phenyl)phenyl]pentan-1-ol.1.5fumaric acid salt

[α]_(D): +15.9 (c 1.16, dimethylformamide),

TLC: Rf 0.30 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 7.63 (d, J=8.3 Hz, 2H), 7.60 (d, J=8.3 Hz, 2H), 7.42(d, J=8.3 Hz, 2H), 7.38 (d, J=8.3 Hz, 2H), 6.57 (s, 3H), 4.54 (t, J=6.0Hz, 1H), 3.71 (s, 2H), 2.34 (s, 6H), 2.26 (t, J=7.2 Hz, 2H), 1.67-1.23(m, 6H), 1.43 (s, 6H).

EXAMPLE 24(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-hydroxyhexanamide

By the same procedure as a series of reactions of reference example4→reference example 3→example 1 using methyl6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-oxohexanoate insteadof the compound prepared in reference example 1, the compound of thepresent invention having the following physical data was obtained.

TLC: Rf 0.50 (chloroform:methanol=9:1),

NMR (CD₃OD): δ 7.52 (d, J=8.7 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 7.36 (d,J=J=8.7 Hz, 2H), 7.00 (d, J=8.7 Hz, 2H), 4.62 (t, J=6.6 Hz, 1H), 4.17(t, J=5.4 Hz, 2H), 3.72 (t, J=4.7 Hz, 4H), 3.28 (s, 3H), 2.82 (t, J=5.4Hz, 2H), 2.61 (t, J=4.7 Hz, 4H), 2.13 (t, J=7.2 Hz, 2H), 1.86-1.70 (m,2H), 1.64 (m, 2H), 1.50-1.23 (m, 2H), 1.33 (s, 6H).

EXAMPLE 24(1)(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)phenyl]-4-hydroxyhexanamide

By the same procedure as a series of reactions of example 24 usingmethyl 6-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)phenyl]-6-oxohexanoateinstead of methyl6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-oxohexanoate, thecompound of the present invention having the following physical data wasobtained.

TLC: Rf 0.46 (chloroform:methanol=9:1),

NMR (CDCl₃): δ 7.70 (brs, 1H), 7.55 (d, J=8.1 Hz, 2H), 7.51 (d, J=8.1Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 4.74-4.69 (m,1H), 3.77-3.73 (m, 4H), 3.30 (s, 3H), 2.87-2.81 (m, 2H), 2.65-2.60 (m,2H), 2.55-2.53 (m, 4H), 2.19-1.32 (m, 8H), 1.41 (s, 6H).

EXAMPLE 25(R)-(+)-N-hydroxy-6-[4-(4-(2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

By the same procedure as a series of reactions of example 2 using thecompound prepared in example 24 instead of the compound prepared inexample 1 and the conversion into the acid addition salts byconventional means., the compound of the present invention having thefollowing physical data was obtained.

[α]_(D): +13.52 (c 0.84, dimethylformamide),

TLC: Rf 0.31 (chloroform:methanol=9:1),

NMR (d₆-DMSO): δ 10.92 (brs, 1H), 10.30 (s, 1H), 8.61 (brs, 1H), 7.61(d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.07(d, J=8.4 Hz, 2H), 5.12 (brs, 1H), 4.53-4.41 (m, 3H), 4.01-3.93 (m, 2H),3.84-3.74 (m, 2H), 3.60-3.12 (m, 6H), 1.90 (t, J=7.2 Hz, 2H), 1.62-1.12(m, 6H).

EXAMPLE 25(1)(R)-(+)-N-hydroxy-6-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)phenyl]-6-hydroxyhexanamide.hydrochloride

By the same procedure as a series of reactions of example 25 using thecompound prepared in example 24(1) or the conversion into the acidaddition salts by conventional means, the compound of the presentinvention having the following physical data was obtained.

[α]_(D): +16.80 (c 0.815, dimethylformamide),

TLC: Rf 0.41 (chloroform:methanol=17:3),

NMR (d₆-DMSO): δ 10.82 (brs, 1H), 10.30 (s, 1H), 8.62 (brs, 1H), 7.62(d, J=8.4 Hz, 2H), 7.58 (d, J=8.4 Hz, 2H), 7.37 (d, J=8.4 Hz, 2H), 7.34(d, J=8.4 Hz, 2H), 5.13 (brs, 1H), 4.53-4.49 (m, 1H), 4.00-3.96 (m, 2H),3.96-3.72 (m, 2H), 3.51-3.47 (m, 2H), 3.39-3.25 (m, 2H), 3.18-3.02 (m,4H), 1.90 (t, J=7.2 Hz, 2H), 1.64-1.16 (m, 6H).

FORMULATION EXAMPLE FORMULATION EXAMPLE 1

The following components were admixed in a conventional technique,punched out to give 100 tablets each containing 50 mg of activeingredient.

(R)-(+)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide 5.0 g

calcium carboxymethylcellulose (disintegrant) 0.2 g

magnesium stearate (lubricant) 0.1 g

microcrystalline cellulose 4.7 g

FORMULATION EXAMPLE 2

The following components were admixed in a conventional technique. Thesolution was sterilized in a conventional technique, filled in ampoules5 ml each and freeze-dried in a conventional technique to give 100ampoules each containing 20 mg of active ingredient.

(R)-(+)-N-hydroxy-6-(4-(4-chlorophenyl)phenyl)-6-hydroxyhexanamide 2.0 g

mannitol 20 g

distilled water 500 mL

What is claimed is:
 1. A hydroxamic acid derivative of the formula (I):

wherein, R¹ is (a) C1-8 alkyl, (b) C2-8 alkenyl, (c) C2-8 alkynyl, (o)C1-8 alkyl substituted by —OR², —SR², —NR³R⁴, —COR⁵ or Cyc1, (u) C1-8alkyl substituted by —O—(C1-8 alkylene)—NR¹²R¹³— or —S—(C1-8alkylene)—NR¹²R¹³, (v) C2-8 alkenyl substituted by —OR², —SR², —NR³R⁴,—COR⁵, Cyc1, nitrile, SO₂R¹⁰, —O—(C1-8 alkylene)—OR¹¹, —O—(C1-8alkylene)—NR¹²R¹³ or —S—(C1-8 alkylene)—NR¹²R¹³ or (w) C2-8 alkynylsubstituted by —OR², —SR², —NR³R⁴, —COR⁵, Cyc1, nitrile, —SO₂R¹⁰,—O—(C1-8 alkylene)—OR¹¹, —O—(C1-8 alkylene)—NR¹²R¹³ or —S—(C1-8alkylene)—NR¹²R¹³, R² is hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1, R³ andR⁴ are each independently hydrogen, C1-8 alkyl, C2-9 acyl or Cyc1, R⁵ ishydroxyl, C1-8 alkyl, C1-8 alkoxy, —NR⁶R⁷ or Cyc1, R⁶ and R⁷ are eachindependently hydrogen, C1-8 alkyl or Cyc1, R¹⁰ is C1-8 alkyl or Cyc1,Cyc1 is morpholine, piperidine or piperazine; R¹¹ is hydrogen, C1-8alkyl, C2-9 acyl or Cyc1; R¹² and R¹³ are each independently hydrogen,C1-8 alkyl, C2-9 acyl or Cyc1; m is an integer of 1-5; ring A is abenzene ring; ring B is a benzene ring; E is a bond, —CH═CH— or —C≡C—;R⁸ is (a) C1-8 alkyl, (b) C1-8 alkoxy, (c) halogen, (d) nitro, (e)nitrile, (f) trifluoromethyl or (g) trifluoromethoxy, with the provisothat when E is a bond then, optionally, R¹ and R⁸, taken together, isC1-4 alkylene; n is 0 or an integer of 1-5; R⁹ is hydrogen, C1-8 alkyl,C2-8 alkenyl or C2-8 alkynyl; a nontoxic salt thereof or a prodrugthereof.
 2. The prodrug of a compound of the formula (I) described inclaim 1, which is represented by the formula (IA):

wherein, R¹⁴ is C1-8 alkyl substituted with C1-8 alkyl, C1-8 alkoxy, theother symbols have the same meaning as defined in claim
 1. 3. Theprodrug of a compound of the formula (I) described in claim 1, which isrepresented by the formula (IB):

wherein, the all symbols have the same meaning as defined in claim
 1. 4.The compound described in claim 1, wherein E is a bond.
 5. The compounddescribed in claim 1, wherein E is —CH═CH— or —C≡C—.
 6. The compounddescribed in claim 1, which is (1)(R)-N-hydroxy-6-[4-(4-(piperidin-1-ylmethyl)phenyl)phenyl]-6-hydroxyhexanamide,(2)(R)-N-hydroxy-6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-hydroxyhexanamide,(3)(R)-N-hydroxy-6-[4-((2-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-hydroxyhexanamide,(4)(R)-N-hydroxy-6-[4-(4-(2-(morpholin-4-yl)ethyl)phenyl)phenyl]-6-hydroxyhexanamideor a nontoxic salt thereof.
 7. The compound described in claim 2, whichis: (1)(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(morpholin-4-ylmethyl)phenyl)phenyl]-6-hydroxyhexanamide,(2)(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(morpholin-4-yl)ethoxy)phenyl)phenyl]-6-hydroxyhexanamide,(3)(R)-N-(1-methoxy-1-methyl)ethoxy-6-[4-(4-(morpholin-4-yl)ethyl)phenyl)phenyl]-6-hydroxyhexanamide,or a nontoxic salt thereof.